Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd

ABSTRACT

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD. Formula (I), wherein A is selected from among a single bond, ═CH—, —CH 2 —, —O—, —S—, and —NH—; wherein n is 1, 2 or 3; wherein Z is C or N, the other variables are as defined in the claims, as well as in form of their acid addition salts with pharmacologically acceptable acids.

FIELD OF INVENTION

The present invention relates to novel antagonists for CCR2 (CCchemokine receptor 2) and their use for providing medicaments fortreating conditions and diseases where activation of CCR2 plays acausative role, especially pulmonary diseases like asthma and COPD,neurologic disease, especially of pain diseases, immune relateddiseases, especially diabetes mellitus including diabetes nephropathy,and cardiovascular diseases, especially atherosclerotic disease.

BACKGROUND OF THE INVENTION

The chemokines are a family of small, proinflammatory cytokines, withpotent chemotactic activities. Chemokines are chemotactic cytokines thatare released by a wide variety of cells to attract various cells, suchas monocytes, macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation.

Chemokine receptors, such as CCR2 or CCR5 have been implicated as beingimportant mediators of inflammatory and immunoregulatory disorders anddiseases as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. Accordingly, agents which modulate chemokinereceptors such as the CCR2 and CCR5 receptor would be useful in suchdisorders and diseases.

In particular it is widely accepted that numerous conditions anddiseases involve inflammatory processes. Such inflammations arecritically triggered and/or promoted by the activity of macrophages,which are formed by differentiation out of monocytes. It has furtherbeen found that monocytes are characterized by, e.g., a high expressionof membrane-resident CCR2, whereas the CCR2 expression in macrophages islower. CCR2 is a critical regulator of monocytes trafficking, which canbe described as the movement of the monocytes towards an inflammationalong a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2,MCP-3, MCP-4).

Therefore, in order to reduce macrophage-induced inflammation, it wouldbe desirable to block the monocyte CCR2 by an antagonist, so that themonocytes can be less triggered to move towards an inflammation area forconversion into macrophages.

Based on the aforesaid there is a need for providing effectiveantagonists for CCR2, which are pharmacologically acceptable.

DESCRIPTION OF THE INVENTION

It has now been found that such effective CCR2 inhibitors can beprovided by compounds according to general formula (I),

wherein R₁ is -L₁-R₇,wherein L₁ is a linker selected from a bond or a group selected from—C₁-C₂-alkylene, and —C₁-C₂-alkenylene which optionally comprises one ormore groups selected from —O—, —C(O)—, and —NH— in the chain and whichis optionally substituted by a group selected from among —OH, —NH₂,—C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —O—CF₃, —CN, and -halogen,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₁-C₆-alkenyl, and —C₁-C₆-alkynyl, optionally being further substitutedby one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O,or wherein the ring R₇ is optionally further bi-valently substituted ontwo neighbouring ring atoms, such that an annellated ring is formed byone or more groups selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two carboncenters may optionally by replaced by 1 or 2 hetero atoms selected fromN, O and S, the bivalent group being optionally substituted by one ormore groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN,—CF₃, —OCF₃, halogen, and ═O;R₂ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂;R₃ is selected from among —H, -methyl, -ethyl, -propyl, -1-propyl,-cyclopropyl, —OCH₃, and —CN;R₄ and R₅ are independently selected from among an electron pair, —H,—C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₅-C₁₀-aryl, —C₅-C₁₀-hetero aryl, and —C(O)—N(R₈,R_(8′)), with R₈ andR_(8′) independently being selected from among —H and —C₁-C₆-alkyl,wherein R₄ and R₅ if different from an electron pair or —H areoptionally independently substituted with one or more groups selectedfrom among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)—O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)—O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylen-N(R₁₂)—O—N(R₁₃,R_(13′)), —C₀-C₄-alkylen-R₁₄,—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇)wherein Q is selected from among —C(O)— and —SO₂—wherein R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,wherein R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′) areindependently selected from among —H and —C₁-C₆-alkyl, and—C₃-C₆-cycloalkyl,or wherein R₉ and R_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ andR_(15′), together form a —C₂-C₆-alkylene group, preferably a—C₅-C₆-alkylene group,wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring, and wherein R₁₄ and R₁₇ areoptionally substituted with one or more groups selected from among —OH,—OCH₃, —CF₃, —OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and—SO₂—C₁-C₄-alkyl,or wherein R₄ and/or R₅ are independently a group of the structure-L₂-R₁₈,wherein L₂ is selected from among —NH—, and —N(C₁-C₄-alkyl)-,wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,wherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl,and wherein R₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein saidspiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring, or wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more spirocyclic or annellated ring forming groupsselected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and—C₄-C₆-alkynylene, in which one or two carbon centers may optionally bereplaced by one or two hetero atoms selected from among N, O and S andwhich may optionally be substituted by one or more groups on one ringatom or on two neighbouring ring atoms selected from among —OH, —NH₂,—C₁-C₃-alkyl, O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen;R₆ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl,-halogen, —CN, —CF₃, and —OCF₃;A is selected from among a single bond, ═CH—, —CH₂—, —O—, —S—, and —NH—;n is 1, 2 or 3;

Z is C or N,

as well as in form of their acid addition salts with pharmacologicallyacceptable acids, as well as in form of their solvates and/or hydrates.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, A, L₂, Z, Q,and n as herein before or below defined, wherein R₁ is -L₁-R₇,

with L₁ being a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene, and —C₁-C₂-alkenylene optionally comprising oneor more groups selected from among —O—, —C(O)—, and, —NH— in the chainand optionally being substituted by a group selected from among —OH,—NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₅-C₁₀-aryl,—C₃-C₈-heterocyclyl comprising 1 or 2 hetero atoms selected from amongN, and O, and —C₅-C₁₀-heteroaryl comprising 1 or 2 hetero atoms selectedfrom among N, and O,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —O—CF₃, —CN, and -halogen,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₁-C₆-alkenyl, and—C₁-C₆-alkynyl, optionally being substituted by one or more groupsselected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃,halogen, and ═O,or wherein the ring R₇ is optionally further bi-valently substituted byone or more annellated ring forming groups selected from among—C₁-C₆-alkylene, —C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which oneor two carbon centers may optionally by replaced by 1 or 2 hetero atomsselected from N, and O, wherein the bivalent group is optionallysubstituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O;

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₂, Z, Q,and n as herein before or below defined, wherein R₁ is -L₁-R₇,

wherein L₁ is a linker selected from among a bond, methylene, ethylene,methenylene, and ethenylene,wherein L₁, if different from a bond, is optionally substituted with oneor more groups selected from among methyl, and ethyl,wherein R₇ is a ring selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl,azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl,pyridyl, and furanyl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —F, —Cl, -methyl, -ethyl, -propyl, -1-propyl,-cyclopropyl, -t-butyl, —CF₃, —O—CF₃, —CN, —O-methyl, -furanyl and-phenyl, wherein said furanyl and said phenyl are optionallyindependently substituted by one or more groups selected from among—C₁-C₆-alkyl, or halogen, —OCH₃, —CF₃, and —OCF₃.or wherein R₇ is bi-valently substituted by one or more groups selectedfrom among

on two neighbouring ring atoms, such that an annellated ring is formed.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₂, Z, Q,and n as herein before or below defined, wherein R₁ is -L₁-R₇,

and wherein L₁ is a linker selected from among a bond, methylene,ethylene, methenylene, and ethenylene and wherein L₁ is optionallysubstituted with one or more of methyl or ethyl and wherein L₁optionally comprises one or more —O— atoms.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, A, L₂, Z, Qand n as herein before or below defined, wherein R₁ is selected fromamong

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₂ is selectedfrom among —H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl,-butyl, -1-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, —C≡CH, and—OCH₃, more preferred from among H, -methyl, -ethyl, -propyl, -1-propyl,-cyclopropyl, and —OCH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R₁₃″, R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z,Q, and n as herein before or below defined, wherein R₂ is selected fromamong —H, -Methyl, -Ethyl, —Br, and —OCH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₃ is selectedfrom among —H, and -methyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂,R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and nas herein before or below defined, wherein R₄ and R₅ are independentlyselected from among an electron pair, —H, -1-propyl, -amino,-pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl,-piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl,-cyclohexyl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′) independentlybeing selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ are optionally independently substituted with one ormore groups selected from among -fluoro, -methyl, -ethyl, propyl,-1-propyl, -butyl, -1-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN,—O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅,—NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃,—N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅,—N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇,—N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅,—N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃,—CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅,—CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅,—CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃,—N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂,—SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅,—C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅,—C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃,—CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl, -pyridin-4-yl,—CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl,-pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl,-3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₄ and R₅ areindependently selected from among an electron pair, —H, -amino,-piperidinyl, -tetrahydropyranyl, and -pyrrolidinyl, wherein R₄ and R₅are optionally independently substituted with one or more groupsselected from among -fluoro, —CF₃, -hydroxy, —O—CH₃, —OCF₃, —CN,—NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃,—NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅,—NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇,—NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅,—CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅,—CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇,—CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂,—NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂,—N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂,—C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉,—C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂,—CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -pyridin-4-yl,—CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl,-pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl,-3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, A, L₁, Z, Q,and n as herein before or below defined, wherein R₄ and R₅ areindependently a group of the structure -L₂-R₁₈, wherein L₂ is selectedfrom among —NH—, —N(CH₃)— and —N(C₂H₅)—, wherein R₁₈ is selected fromamong -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyrano-pyrrolyl,-octahydro-pyrano-pyridinyl, -octahydro-pyrano-oxazinyl,-oxaspirodecanyl, and -tetrahydro-naphthyridinyl,

wherein R₁₈ is optionally substituted by one or more groups selectedfrom among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃, —NH—C(O)—CH₃,—N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃,—N(CH₃)—S(O)₂—CH₃, and —C(O)—O—C₂H₅.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀,R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A,L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₄, R₅and R₁₈ are optionally further bi-valently substituted by one or moregroups selected from among

on one ring atom or on two neighboring ring atoms, such that spirocyclicor annellated rings are formed.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₄ is selectedfrom among

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₅ is selectedfrom among an electron pair, —H, and —C(O)—NH₂.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂,Z, Q, and n as herein before or below defined, wherein R₆ is selectedfrom among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F, —CF₃, and —OCF₃, andmore preferred wherein R₆ is selected from among H, and —O—CH₃, and mostpreferred wherein R₆ is —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀,R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, L₁,L₂, Z, Q, and n as herein before or below defined, wherein A is selectedfrom among a single bond, ═CH—, —CH₂, —O—, and —NH—, and more preferredwherein A is selected from among —O— and —NH—, and most preferredwherein A is —NH—.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀,R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A,L₁, L₂, Q, and n as herein before or below defined, wherein Z isselected from among C, and N, and more preferred wherein Z is C.

All of the above embodiments under formula (I) have to be understood tooptionally be present in form of their individual optical isomers,mixtures of their individual optical isomers, or racemates, as well asin form of their acid addition salts with pharmacologically acceptableacids, as well as in form of their solvates and/or hydrates.

DEFINITIONS

Unless otherwise stated, all the substituents are independent of oneanother. If for example there might be a plurality of C₁-C₆-alkyl groupsas substituents in one group, in the case of three substituentsC₁-C₆-alkyl, one may represent methyl, one n-propyl and one tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Moreover, the atom of the substituent which follows the linking point isreferred to as the atom in position number 1. Thus, for example, thegroups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl(Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown asfollows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed from the substituent andthe valency thus freed may act as a binding site to the rest of amolecule. Thus, for example, (Tolyl-F) may represent 2-tolyl, 3-tolyl,4-tolyl, and benzyl

By the term “branched or unbranched, saturated or unsaturatedC₁-C₆-carbon chain” it is meant a chain of carbon atoms, which isconstituted by six carbon atoms arranged in a row and which canoptionally further comprise branches or one or more hetero atomsselected from N, O or S. Said carbon chain can be saturated orunsaturated by comprising double or triple bonds.

By the term “C₁-C₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁-C₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples for alkyl groups with 1-6 carbonatoms include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl.Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc.may also be used for the above-mentioned groups. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁-C₈-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 8carbon atoms. By the term “C₂-C₈-alkylene” are meant branched andunbranched alkylene groups with 2 to 8 carbon atoms. By the term“C₂-C₆-alkylene” are meant branched and unbranched alkylene groups with2 to 6 carbon atoms. By the term “C₁-C₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. By the term“C₁-C₂-alkylene” are meant branched and unbranched alkylene groups with1 to 2 carbon atoms. By the term “C₀-C₄-alkylene” are meant branched andunbranched alkylene groups with 0 to 4 carbon atoms, thus also a singlebond is encompassed. By the term “C₁-C₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples forC₁-C₈-alkylene include: methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene, heptylene or octylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene, hexylene, heptylene andoctylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propyl alsoincludes 1-methylethylene and butylene includes 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene.

If the carbon chain is to be substituted by a group which together withone or two carbon atoms of the alkylene chain forms a carbocyclic ringwith 3, 5 or 6 carbon atoms, this includes the following examples of therings:

By the term “C₂-C₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples for C₂-C₆-alkenyls include: ethenyl or vinyl,propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, thedefinitions propenyl, butenyl, pentenyl and hexenyl include all thepossible isomeric forms of the groups in question. Thus, for example,propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “methenylene” is meant a group with 1 carbon atom, providedthat it is linked by a single bond as well as on the other side by adouble bond:

By the term “C₂-C₈-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkenylene” are meant branched andunbranched alkylene groups with 2 to 6 carbon atoms. By the term“C₁-C₂-alkenylene” are meant alkenylene groups with 1 to 2 carbon atoms,provided that they have at least one double bond, whereas by the term“C₁-alkenylene” is meant “methenylene”. Examples for C₂-C₈-alkenylenesinclude: ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene,heptenylene or octenylene. Unless stated otherwise, the definitionspropenylene, butenylene, pentenylene and hexenylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propenyl also includes 1-methylethenyleneand butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene.

By the term “C₂-C₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Examples for C₂-C₆-alkynyls include:ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless statedotherwise, the definitions propynyl, butynyl, pentynyl and hexynylinclude all the possible isomeric forms of the groups in question. Thusfor example propynyl includes 1-propynyl and 2-propynyl, butynylincludes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyletc.

By the term “C₂-C₈-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkynylene” are meant branched andunbranched alkylene groups with 2 to 6 carbon atoms. Examples ofC₂-C₈-alkynylenes include: ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene, heptynylene or octynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

By the term “ring” are meant carbocycles, which can be saturated,unsaturated or aromatic and which optionally can comprise one or morehetero atoms selected from N, O or S.

By the term “—C₃-C₈-heterocyclyl” are meant three-, four-, five-, six-,or seven-membered, saturated or unsaturated heterocyclic rings which maycontain one, two, or three heteroatoms, selected from among oxygen,sulfur, and nitrogen, while the ring may be linked to the moleculethrough a carbon atom or through a nitrogen atom, if there is one. Bythe term “—C₅-C₈-heterocyclyl” are meant five-, six-, or seven-membered,saturated or unsaturated heterocyclic rings which may contain one, two,or three heteroatoms, selected from among oxygen, sulfur, and nitrogen,while the ring may be linked to the molecule through a carbon atom orthrough a nitrogen atom, if there is one. Examples include:

Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) maybe provided with a keto group. Examples include:

By the term “C₃-C₈-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 8 carbon atoms.Likewise, by the term “C₃-C₆-cycloalkyl” are meant cyclic alkyl groupswith 3 to 6 carbon atoms. Examples of C₃-C₈-cycloalkyls include:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems. By the term “C₅-C₁₀-aryl” (including thosewhich are part of other groups) are meant aromatic ring systems with 5to 10 carbon atoms. Preferred are “C₆-C₁₀-aryl” groups whereas aromaticrings are meant with 6 to 10 carbon atoms. Examples include: phenyl ornaphthyl. Also preferred are “C₅-C₆-aryl” groups whereas aromatic ringsare meant with 5 to 6 carbon atoms Unless otherwise stated, the aromaticring systems may be substituted by one or more groups selected fromamong methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine,chlorine, bromine and iodine.

By the term “C₅-C₁₀-heteroaryl” (including those which are part of othergroups) are meant five- or six-membered heterocyclic aromatic groups or5-10-membered, bicyclic heteroaryl rings which may contain one, two, orthree heteroatoms selected from among oxygen, sulfur, and nitrogen, andcontain so many conjugated double bonds that an aromatic system isformed. The following are examples of five- or six- or nine-memberedheterocyclic aromatic groups:

Preferred are “C₅-C₆-heteroaryl” groups whereas aromatic rings are meantfive- or six-membered heterocyclic aromatic groups. Unless otherwisestated, these heteroaryls may be substituted by one or more groupsselected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy,fluorine, chlorine, bromine, and iodine.

When a generic combined groups are used, for example —X—C₁-C₄-alkyl-with X being a functional group such as —CO—, —NH—, —C(OH)— and thelike, the functional group X can be located at either of the ends of the—C₁-C₄-alkyl chain.

By the term “spiro-C₃-C₈-cycloalkyl” (spiro) are meant 3-8 membered,spirocyclic rings while the ring is linked to the molecule through acarbon atom. By the term “spiro-C₃-C₈-heterocyclyl” (spiro) are meant3-8 membered, spirocyclic rings which may contain one, two, or threeheteroatoms selected from among oxygen, sulfur, and nitrogen, while thering may be linked to the molecule through a carbon atom or through anitrogen atom, if there is one.

Unless otherwise mentioned, a spirocyclic ring may be provided with anoxo, methyl, or ethyl group. Examples include:

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

“Linker” within the scope of the present invention denominates abivalent group or a bond.

The above listed groups and residues can be combined to form morecomplex structures composed from carbon chains and rings or the like.

Compounds of general formula (I) may have acid groups, chiefly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula (I) may therefore occur as internal salts, as salts withpharmaceutically useable inorganic acids such as hydrochloric acid,sulphuric acid, phosphoric acid, sulphonic acid or organic acids (suchas for example maleic acid, fumaric acid, citric acid, tartaric acid oracetic acid) or as salts with pharmaceutically useable bases such asalkali or alklaline earth metal hydroxides or carbonates, zinc orammonium hydroxides or organic amines such as e.g. diethylamine,triethylamine, triethanolamine inter alia.

As mentioned hereinbefore, the compounds of formula (I) may be convertedinto the salts thereof, particularly for pharmaceutical use, into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may on the one hand be in the form of the physiologically andpharmacologically acceptable acid addition salts of the compounds offormula (I) with inorganic or organic acids. On the other hand, if R ishydrogen, the compound of formula (I) may also be converted by reactionwith inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations as counterion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. The alkali and alkaline earthmetal salts of the compound of formula (I) are preferably prepared usingthe alkali and alkaline earth metal hydroxides and hydrides thereof, ofwhich the hydroxides and hydrides of the alkaline earth metals,particularly of sodium and potassium, are preferred and sodium andpotassium hydroxide are particularly preferred.

If desired, the compounds of general formula (I) may be converted intothe salts thereof, particularly, for pharmaceutical use, into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Suitable acids include for example succinic acid,hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to the invention may optionally occur asracemates, but they may also be obtained as pureenantiomers/diastereomers.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to formula (I) according to the invention havethe meanings hereinbefore whereas in particular the preferredembodiments defined by R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R_(9′), R₁₀,R₁₁, R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₁,L₂, Z, Q, and n in each case are independently selected of one another.

Therapeutic Applications

The above exemplary substances have been tested for binding to CCR2using a binding assay as outlined herein below:

Cell Culture:

THP-1 cells (human acute monocytic leukaemia cells) were cultured understandardized conditions at 37° C. and 5% CO2 in a humidified incubator.THP-1 cells were cultivated in RPMI 1640 medium (Gibco 21875) containing1% MEM-NEAA (Gibso 11140) 2 mM L-glutamine, 1.5 g/L sodium bicarbonate,4.5 g/L glucose, 10 mM HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetalcalf serum (FCS Gibco 10500-064). Membranes were prepared from THP-1cells. THP-1 cells were centrifuged at 300×g at 4° C. for 10 min. Thecell pellet was resuspendet in Phosphate Buffer Saline (PBS , including10 μM Pefabloc and a protease inhibitor mix ‘complete’, BoehringerMannheim (1 tablet/50 ml)), to a concentration of 80 cells/ml. Themembrane preparation was performed by disrupting the cells by nitrogendecomposition (at 50 bar, for 1 h) in a “Nitrogen Bombe” (ParrInstrument). Cell debris was removed by centrifugation (800×g at 4° C.,1 min). The supernatant was centrifuged at 80000×g , 4° C. for 30 min tosediment the cell membranes . Usually 50 mg of protein (Bradford assay)were yielded from 1×10E9 cells. The membranes were resuspendet in 25 mMHEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine for storage in aliquots at−80° C. in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine andstored at −80° C.

Receptor Membrane Binding Assay:

Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol solved in 2000μl assay buffer, stored at −20° C. THP-1 membrane were adjusted with 25mM HEPES, pH 7.2; 5 mM MgCl₂; 0.5 mM CaCl₂; 0.2% BSA assay buffer to aconcentration of 2.5 μg/15 μl. Amersham Biosciences PVT-WGA Beads(RPNQ0001) were adjusted with assay buffer to a concentration of 0.24mg/30 μl. For preparation of the membrane-bead-suspension membranes andbeads were incubated for 30 min at RT under rotation (60 rpm) with aratio of 1:2. Test compounds dissolved in 100% DMSO to a concentrationof 10 mM and are further diluted with 100% DMSO to 1 mM. All additionalcompound dilutions were obtained with assay buffer, final 1% DMSO.Compounds, membrane-bead-suspension and [125I]MCP-1 (ca. 25000 cpm/10μl) were incubated. Bound radioactivity was determined by scintillationcounter after 8 h. Determination of affinity of test compounds(dissociation constant hKi) is calculated by iterative fitting ofexperimental data using the “easy sys” program, which is based on law ofmass action (Schittkowski K. (1994), Numerische Mathematik, Vol. 68,129-142).

All of the above-referenced examples have been found to have an activityin this assay of 10 μM or less.

CCR2 % ctrl CCR2 % ctrl Example hKi @ 10 μM Example hKi @ 10 μM  1 32 1 15 200 14  2 222 13  16 1904 40  3 204 14  17 302 18  4 1593 43  183505 52  5 616 26  19 269 40  6 1928 41  20 303 24  7 306 16  21 2660 51 8 1023 36  22 466 24  9 974 32  23 169 7  10 650 27  24 4029 58  111710 38  25 2406 47  12 664 29  26 914 30  13 1332 42  27 620 25  14 38722  28 4176 58  29 2097 40  59 55 5  30 446 18  60 44 5  31 790 28  6146 2  32 37 2  62 38 3  33 22 0  63 54 7  34 62 4  64 65 8  35 24 5  65176 8  36 10 1  66 138 8  37 11 4  67 1423 27  38 69 13  68 98 7  39 362  69 63 7  40 174 9  70 80 6  41 11 6  71 117 12  42 433 16  72 81 7 43 566 17  73 38 2  44 1639 27  74 71 2  45 501 17  75 67 7  46 225 12 76 132 12  47 222 14  77 650 27  48 1778 26  78 740 28  49 97 7  79 8910  50 928 22  80 53 7  51 290 13  81 52 8  52 175 12  82 43 4  53 18 4 83 43 3  54 356 13  84 69 4  55 200 17  85 55 13  56 127 8  86 39 3  5793 10  87 78 9  58 336 12  88 58 6  89 770 29 119 1033 37  90 127 10 120499 30  91 236 23 121 147 15  92 175 14 122 415 23  93 123 6 123 542 26 94 211 8 124 361 20  95 170 2 125 446 25  96 939 21 126 399 23  97 66517 127 665 35  98 214 2 128 445 26  99 1826 32 129 336 21 100 395 18 1304266 50 101 986 35 131 55 6 102 224 15 132 672 31 103 1605 30 133 205 15104 617 31 134 399 23 105 687 31 135 888 19 106 405 13 136 773 14 107232 12 137 634 14 108 627 20 138 145 6 109 213 11 139 443 9 110 527 28140 692 16 111 464 27 141 422 7 112 378 21 142 529 8 113 3306 46 143 4228 114 62 8 144 91 7 115 847 33 145 181 17 116 198 16 146 3 7 117 285 19147 40 8 118 2162 41 148 119 4 149 41 10 179 1637 42 150 12 3 189 481260 151 14 7 181 3607 58 152 44 7 182 2991 53 153 27 1 183 426 45 154 12315 184 908 30 155 76 8 185 4209 53 156 18 8 186 78 8 157 1147 23 187 25615 158 6 0 188 3934 53 159 25 4 189 170 13 160 43 3 190 783 27 161 199630 191 519 20 162 3798 43 192 1446 37 163 1560 32 193 1536 35 164 353 15194 491 25 165 222 15 195 141 14 166 227 16 196 666 19 167 246 16 197 334 168 51 9 198 58 1 169 2287 54 199 534 9 170 705 31 200 108 5 171 35616 201 101 6 172 736 28 202 292 7 173 89 6 203 641 11 174 2718 53 204123 6 175 434 14 205 135 11 176 648 31 206 44 3 177 1252 43 207 1180 35178 27 0 208 99 7 209 177 7 239 2319 33 210 83 0 240 104 7 211 140 5 241522 21 212 731 24 242 516 21 213 430 14 243 1615 40 214 711 20 244 36624 215 2146 42 245 555 15 216 4283 59 246 306 2 217 4326 54 247 149 6218 281 8 248 576 17 219 476 22 249 3249 36 220 979 27 250 1263 32 221172 12 251 439 75 222 1306 31 252 38 6 223 244 14 253 350 17 224 1230 35254 101 11 225 21 0 255 33 5 226 1170 36 256 438 25 227 333 22 257 18614 228 331 16 258 64 4 229 1133 39 259 277 16 230 1845 45 260 493 20 231215 15 261 120 8 232 924 34 262 224 13 233 194 8 263 1968 27 234 401 19264 41 3 235 460 26 265 462 23 236 175 14 266 149 237 133 9 267 487 20238 239 14 268 119 5 228a 1564 9 228e 3720 40 228b 2 4 228f 15 1 228c 290 228g 169 6 228d 91 1 228h 5 0 269 2340 36 285 1306 35 270 179 9 286965 19 271 1608 15 287 2547 33 272 155 8 288 738 13 273 1435 27 289 166734 274 4421 48 290 1601 28 275 593 19 291 3123 32 276 1842 23 292 136 15277 1376 34 293 717 27 278 1078 32 294 230 16 279 192 9 295 140 0 2801435 32 296 69 3 281 1012 24 297 164 10 282 1527 39 298 599 17 283 442148 299 70 6 284 1514 42 300 136 8 275a 29 0 275c 2932 38 275b 26 3 275d318 10 Example hKi Example hKi 228go 54 159e 28 228gp 1354 159f 14 228ga23 159g 15 228gb 3828 159h 39 228gc 561 159i 24 228gd 1094 159k 22 228ge37 159l 22 228gf 145 159m 9 228gg 1026 159n 233 228gh 4066 159o 12 228gi1101 159p 7 228gj 55 159q 10 228gk 44 159r 2578 228gl 537 159s 1314228gm 28 159t 1202 228gn 333 159u 29 275da 4 159w 9 275db 33 159y 169275dc 11 159x 147 275dd 40 159z 11 275de 16 159aa 18 275df 15 159ba 11275dg 12 159ca 3 275dh 3 159da 5 275di 1 159ea 7 275dj 4 159fa 35 159a10 159ga 28 159b 7 159ha 27 159c 13 159ia 17 159d 15 159ja 18 159ka 19159pb 10 159la 19 159qb 69 159ma 20 159rb 54 159na 21 159sb 21 159oa 29159tb 13 159pa 32 159ub 18 159qa 19 159wb 16 159ra 22 159yb 15 159sa 22159xb 6 159ta 27 159zb 15 159ua 23 159ac 5936 159wa 33 159bc 3492 159ya18 159cc 10 159xa 21 159dc 38 159za 6 159ec 961 159ab 27 159fc 13 159bb48 159gc 26 159cb 39 228ha 32 159db 16 301 22 159eb 72 302 32 159fb 199275dk 17 159gb 39 275dl 372 159hb 20 159ib 15 159jb 39 159kb 24 159lb 12159mb 14 159nb 88 159ob 118

Based on the ability of the substances described by formula (I) toeffectively bind to CCR2a range of therapeutic applications can beenvisaged. The present invention provides a method for modulating ortreating at least one MCP-1 related disease, in a cell, tissue, organ,animal, or patient, as known in the art or as described herein, using atleast one CCR2 antagonist of the present invention. The presentinvention also provides a method for modulating or treating at least oneMCP-1 related disease, in a cell, tissue, organ, animal, or patientincluding, but not limited to, at least one of malignant disease,metabolic disease, an immune or inflammatory related disease, acardiovascular disease, an infectious disease, or a neurologic disease.Such conditions are selected from, but not limited to, diseases orconditions mediated by cell adhesion and/or angiogenesis. Such diseasesor conditions include an immune disorder or disease, a cardiovasculardisorder or disease, an infectious, malignant, and/or neurologicdisorder or disease, or other known or specified MCP-1 relatedconditions. In particular, the CCR2 antagonists are useful for thetreatment of diseases that involve inflammation such as COPD,angiogenesis such as disease of the eye and neoplastic disease, tissueremodeling such as restenosis, and proliferation of certain cells typesparticularly epithelial and squamous cell carcinomas. Particularindications include use in the treatment of atherosclerosis, restenosis,cancer metastasis, rheumatoid arthritis, diabetic retinopathy andmacular degeneration. The antagonists may also be useful in thetreatment of various fibrotic diseases such as idiopathic pulmonaryfibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Thus, thepresent invention provides a method for modulating or treating at leastone CCR2 related disease, in a cell, tissue, organ, animal, or patient,as known in the art or as described herein, using at least one CCR2antagonist of the present invention. Particular indications arediscussed below:

Pulmonary Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: pneumonia; lungabscess; occupational lung diseases caused be agents in the form ordusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans,respiratory failure, hypersensitivity diseases of the lungs iricludeinghypersensitivity pneumonitis (extrinsic allergic alveolitis), allergicbronchopulmonary aspergillosis, and drug reactions; adult respiratorydistress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructiveairway disorders (COPD), idiopathic interstitial lung diseases such asidiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitialpneumonia, acute interstitial pneumonia, respiratorybronchiolitis-associated interstitial lung disease, idiopathicbronchiolitis obliterans with organizing pneumonia, lymphocyticinterstitial pneumonitis, Langerhans' cell granulomatosis, idiopathicpulmonary hemosiderosis; acute bronchitis, pulmonary alveolar,proteinosis, bronchiectasis, pleural disorders, atelectasis, cysticfibrosis, and tumors of the lung, and pulmonary embolism.

Malignant Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: leukemia, acuteleukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL,acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chroniclymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome(MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma,non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi'ssarcoma, colorectal carcinoma, pancreatic carcinoma, renal cellcarcinoma, breast cancer, nasopharyngeal carcinoma, malignanthistiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy,solid tumors, adenocarcinomas, squamous cell carcinomas, sarcomas,malignant melanoma, particularly metastatic melanoma, hemangioma,metastatic disease, cancer related bone resorption, cancer related bonepain, and the like.

Immune Related Diseases

The present invention also provides a method for modulating or treatingat least one immune related disease, in a cell, tissue, organ, animal,or patient including, but not limited to, at least one of rheumatoidarthritis, juvenile rheumatoid arthritis, systemic onset juvenilerheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis,gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatorybowel disease, ulcerative colitis, systemic lupus erythematosis,antiphospholipid syndrome, iridocyclitisluveitisloptic neuritis,idiopathic pulmonary fibrosis, systemic vasculitis/wegener'sgranulomatosis, sarcoidosis, orchitislvasectomy reversal procedures,allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergiccontact dermatitis, allergic conjunctivitis, hypersensitivitypneumonitis, transplants, organ transplant rejection, graft-versus-hostdisease, systemic inflammatory response syndrome, sepsis syndrome, grampositive sepsis, gram negative sepsis, culture negative sepsis, fungalsepsis, neutropenic fever, urosepsis, meningococcemia,traumalhemo˜˜hage, burns, ionizing radiation exposure, acutepancreatitis, adult respiratory distress syndrome, rheumatoid arthritis,alcohol-induced hepatitis, chronic inflammatory pathologies,sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis,atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever,perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria,systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic diseases,thrombocytopenia, graft rejection of any organ or tissue, kidneytransplant rejection, heart transplant rejection, liver transplantrejection, pancreas transplant rejection, lung transplant rejection,bone marrow transplant (BMT) rejection, skin allograft rejection,cartilage transplant rejection, bone graft rejection, small boweltransplant rejection, fetal thymus implant rejection, parathyroidtransplant rejection, xenograft rejection of any organ or tissue,allograft rejection, anti-receptor hypersensitivity reactions, Gravesdisease, Raynoud's disease, type B insulin-resistant diabetes, asthma,myasthenia gravis, antibody-meditated cytotoxicity, type IUhypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), polyneuropathy, organomegaly,endocrinopathy, monoclonal garnrnopathy, skin changes syndrome,antiphospholipid syndrome, pemphigus, scleroderma, mixed connectivetissue disease, idiopathic Addison's disease, diabetes mellitus, chronicactive hepatitis, primary billiary cirrhosis, vitiligo, vasculitis,post-MI cardiotomy syndrome, type IV hypersensitivity , contactdermatitis, hypersensitivity pneumonitis, allograft rejection,granulomas due to intracellular organisms, drug sensitivity,metabolic/idiopathic, Wilson's disease, hemachromatosis,alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto'sthyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axisevaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis,cachexia, cystic fibrosis, neonatal chronic lung disease, chronicobstructive pulmonary disease (COPD), familial hematophagocyticlymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,nephrotic syndrome, nephritis, glomerular nephritis, acute renalfailure, hemodialysis, uremia, toxicity, preeclampsia, OKT3 therapy,anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy(e.g., including but not limited toasthenia, anemia, cachexia, and thelike), chronic salicylate intoxication, and the like.

Cardiovascular Diseases

The present invention also provides a method for modulating or treatingat least one cardiovascular disease in a cell, tissue, organ, animal, orpatient, including, but not limited to, at least one of cardiac 25 stunsyndrome, myocardial infarction, congestive heart failure, stroke,ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis,restenosis, diabetic ateriosclerotic disease, hypertension, arterialhypertension, renovascular hypertension, syncope, shock, syphilis of thecardiovascular system, heart failure, cor pulmonale, primary pulmonaryhypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter,atrial fibrillation (sustained or paroxysmal), post perfusion syndrome,cardiopulmonary bypass inflammation response, chaotic or multifocalatrial tachycardia, regular narrow QRS tachycardia, specific arrythmias,ventricular fibrillation, His bundle arrythmias, atrioventricular block,bundle branch block, myocardial ischemic disorders, coronary arterydisease, angina pectoris, myocardial infarction, cardiomyopathy, dilatedcongestive cardiomyopathy, restrictive cardiomyopathy, valvular heartdiseases, endocarditis, pericardial disease, cardiac tumors, aordic andperipheral aneuryisms, aortic dissection, inflammation of the aorta,occulsion of the abdominal aorta and its branches, peripheral vasculardisorders, occulsive arterial disorders, peripheral atherloscleroticdisease, thromboangitis obliterans, functional peripheral arterialdisorders, Raynaud's phenomenon and disease, acrocyanosis,erythromelalgia, venous diseases, venous thrombosis, varicose veins,arteriovenous fistula, lymphederma, lipedema, unstable angina,reperfusion injury, post pump syndrome, ischemia-reperfusion injury, andthe like. Such a method can optionally comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one CCR2 antagonist to a cell, tissue, organ, animalor patient in need of such modulation, treatment or therapy.

Neurologic Diseases

The present invention also provides a method for modulating or treatingat least one neurologic disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: Neuropathicpain such as low back pain, hip pain, leg pain, non-herpetic neuralgia,post herpetic neuralgia, diabetic neuropathy, nerve injury-induced pain,acquired immune deficiency syndrome (AIDS) related neuropathic pain,head trauma, toxin and chemotherapy caused nerve injuries, phantom limbpain, multiple sclerosis, root avulsions, painful traumaticmononeuropathy, painful polyneuropathy, thalamic pain syndrome,post-stroke pain, central nervous system injury, post surgical pain,carpal tunnel syndrome, trigeminal neuralgia, post mastectomy syndrome,postthoracotomy syndrome, stump pain, repetitive motion pain,neuropathic pain associated hyperalgesia and allodynia, alcoholism andother drug-induced pain; neurodegenerative diseases, multiple sclerosis,migraine headache, AIDS dementia complex, demyelinating diseases, suchas multiple sclerosis and acute transverse myelitis; extrapyramidal andcerebellar disorders' such as lesions of the corticospinal system;disorders of the basal ganglia or cerebellar disorders; hyperkineticmovement disorders such as Huntington's Chorea and senile chorea;drug-induced movement disorders, such as those induced by drugs whichblock CNS dopamine receptors; hypokinetic movement disorders, such asParkinson's disease; Progressive supra-nucleo Palsy; structural lesionsof the cerebellum; spinocerebellar degenerations, such as spinal ataxia,Friedreich's ataxia, cerebellar cortical degenerations, multiple systemsdegenerations (Mencel, Dej erine-Thomas, Shi-Drager, andMachado-Joseph); systemic disorders (Refsum's disease,abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multisystem disorder); demyelinating core disorders, such as multiplesclerosis, acute transverse myelitis; and disorders of the motor unit'such as neurogenic muscular atrophies (anterior horn cell degeneration,such as amyotrophic lateral sclerosis, infantile spinal muscular atrophyand juvenile spinal muscular atrophy); Alzheimer's disease; Down'sSyndrome in middle age; Diffuse Lewy body disease; Senile Dementia ofLewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism;Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis,Hallerrorden-Spatz disease; and Dementia pugilistica, and the like.

Fibrotic Conditions

In addition to the above described conditions and diseases, the presentinvention also provides a method for modulating or treating fibroticconditions of various etiologies such as liver fibrosis (including butnot limited to alcohol-induced cirrhosis, viral-induced cirrhosis,autoirnrnune-induced hepatitis); lung fibrosis (including but notlimited to scleroderma, idiopathic pulmonary fibrosis); kidney fibrosis(including but not limited to scleroderma, diabetic nephritis,glomerular pehpritis, lupus nephritis); dermal fibrosis (including butnot limited to scleroderma, hypertrophic and keloid scarring, burns);myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; andfibrotic adhesions resulting from surgical procedures.

The present invention also provides a method for modulating or treatingat least one wound, trauma or tissue injury or chronic conditionresulting from or related thereto, in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: bodily injuryor a trauma associated with surgery including thoracic, abdominal,cranial, or oral surgery; or wherein the wound is selected from thegroup consisting of aseptic wounds, contused wounds, incised wounds,lacerated wounds, non-penetrating wounds, open wounds, penetratingwounds, perforating wounds, puncture wounds, septic wounds, infarctionsand subcutaneous wounds; or wherein the wound is selected from the groupconsisting of ischemic ulcers, pressure sores, fistulae, severe bites,thermal burns and donor site wounds; or wherein the wound is anaphthouswound, a traumatic wound or a herpes associated wound. Donor site woundsare wounds which e.g. occur in connection with removal of hard tissuefrom one part of the body to another part of the body e.g. in connectionwith transplantation. The wounds resulting from such operations are verypainful and an improved healing is therefore most valuable. Woundfibrosis is also amenable to CCR2 antagonist therapy as the first cellsto invade the wound area are neutrophils followed by monocytes which areactivated by macrophages. Macrophages are believed to be essential forefficient wound healing in that they also are responsible forphagocytosis of pathogenic organisms and a clearing up of tissue debris.Furthermore, they release numerous factors involved in subsequent eventsof the healing process. The macrophages attract fibroblasts which startthe production of collagen. Almost all tissue repair processes includethe early connective tissue formation, a stimulation of this and thesubsequent processes improve tissue healing, however, overproduction ofconnective tissue and collegen can lead to a fibrotic tissuecharacterized as inelastic and hypoxic. The CCR2 antagonist of theinvention can be used in methods for modulating, treating or preventingsuch sequelae of wound healing.

Other Therapeutic Uses of CCR2 Antagonists

The present invention also provides a method for modulating or treatingat least one infectious disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: acute orchronic bacterial infection, acute and chronic parasitic or infectiousprocesses, including bacterial, viral and fungal infections, HIVinfection, HIV neuropathy, meningitis, hepatitis (A, B or C, or thelike), septic arthritis, peritonitis, pneumonia, epiglottitis, e. coli0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenicpurpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy,toxic shock syndrome, streptococcal myositis, gas gangrene,mycobacterium tuberculosis, mycobacterium avium intracellulare,pneumocystis carinii pneumonia, pelvic inflammatory disease,orchitislepidydimitis, legionella, lyme disease, influenza a,epstein-barr virus, vital-associated hemaphagocytic syndrome, vitalencephalitisiaseptic meningitis, and the like.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one CCR2 antagonist to a cell, tissue, organ, animalor patient in need of such modulation, treatment or therapy.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like.

Combinations

The compounds of formula I may be used on their own or in conjunctionwith other active substances of formula I according to the invention. Ifdesired the compounds of formula I may also be used in combination withother pharmacologically active substances. It is preferable to use forthis purpose active substances selected for example from amongbetamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or doubleor triple combinations thereof, such as for example combinations ofcompounds of formula I with one or two compounds selected from among

-   -   betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors        and LTD4-antagonists,    -   anticholinergics, betamimetics, corticosteroids,        PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,    -   PDE4-inhibitors, corticosteroids, EGFR-inhibitors and        LTD4-antagonists    -   EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists    -   EGFR-inhibitors and LTD4-antagonists    -   —CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide        synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin        (hereinafter referred to as “BH4”) and the derivatives thereof        as mentioned in WO 2006/120176 and SYK-inhibitors (spleen        tyrosine kinase-inhibitors)    -   anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors        and MRP4-inhibitors.

The invention also encompasses combinations of three active substances,each selected from one of the above-mentioned categories of compounds.

The betamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol,tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Preferably the beta mimetics are selected from among bambuterol,bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,sulphonterol, terbutaline, tolubuterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Of these betamimetics those which are particularly preferred accordingto the invention are formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoateand hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxy-fluorene-9-carboxylate -methobromide, tropenol9-fluoro-fluorene-9-carboxylate -methobromide, scopine9-hydroxy-fluoren-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide, tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, methyl -cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate -methobromide,scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate methobromide, scopine9-methyl-xanthene-9-carboxylate methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in theform of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S -yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulphobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compoundsselected from among enprofyllin, theophyllin, roflumilast, ariflo(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram,D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888,YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from amongenprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram,AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, Cl-1018,CDC-801, D-22888, YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast,pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507),VUF-5078, VUF-K-8707 and L-733321, optionally in the form of theracemates, enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 andMEN-91507 (LM-1507), optionally in the form of the racemates,enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the formof the racemates, enantiomers or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition salts, thesolvates and/or hydrates thereof.

Preferred EGFR inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and Cetuximab, optionally in the form of the racemates, enantiomers ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts, the solvates and/or hydrates thereof.

It is particularly preferable within the scope of the present inventionto use those EGFR-inhibitors which are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

Particularly preferred EGFR-inhibitors according to the invention arethe compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazolineoptionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-β-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate, MK571((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside,probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate,taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholicacid sulphate, topotecan,

trequinsin and zaprinast, dipyridamole, optionally in the form of theracemates, enantiomers, diastereomers and the pharmacologicallyacceptable acid addition salts and hydrates thereof.

Preferably the invention relates to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for the treatment of respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitors, theMRP4-inhibitors preferably being selected from amongN-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulphate,flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen,indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833,sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate,taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers andthe pharmacologically acceptable acid addition salts and hydratesthereof.

The invention relates more preferably to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for treating respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitorsaccording to the invention, the MRP4-inhibitors preferably beingselected from among dehydroepiandrosterone 3-sulphate, estradiol3,17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571,taurocholate, optionally in the form of the racemates, enantiomers,diastereomers and the pharmacologically acceptable acid addition saltsand hydrates thereof. The separation of enantiomers from the racematescan be carried out using methods known from the art (e.g. chromatographyon chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the PDE4B-inhibitors, MRP4-inhibitorsand another active substance according to the invention, such as, forexample, an anticholinergic, a steroid, an LTD4-antagonist or abetamimetic, and the preparation thereof and the use thereof fortreating respiratory complaints.

The iNOS-inhibitors used are preferably compounds selected from among:S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT,L-canavanine, 2-iminopiperidine, S-isopropylisothiourea,S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrulline,S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME(N^(ω)-nitro-L-arginine methylester), L-NMMA(N^(G)-monomethyl-L-arginine), L-NIO (N^(ω)-iminoethyl-L-ornithine),L-NIL (N^(ω)-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoicacid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,1686-1689), 1400W,(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinaminessuch as e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916),(1S,5S,6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl3-{[(benzo[1.3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1.3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Other iNOS-inhibitors which may be used within the scope of the presentinvention are antisense oligonucleotides, particularly antisenseoligonucleotides that bind iNOS-coding nucleic acids. For example, WO01/52902 describes antisense oligonucleotides, particularlyantisense-oligonucleotides, which bind iNOS-coding nucleic acids, formodulating the expression of iNOS. Those iNOS-antisense-oligonucleotidesas described particularly in WO 01/52902 may therefore also be combinedwith the PDE4-inhibitors of the present invention on the basis of theirsimilar activity to the iNOS inhibitors.

Compounds which may be used as SYK-inhibitors are preferably compoundsselected from among: R343 or R788.

Pharmaceutical Formulations

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised inthat they contain one or more compounds of formula I according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula I areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula I are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula I have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula I are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain 1 dissolved in the propellant gas or indispersed form. The propellant gases which may be used to prepare theinhalation aerosols according to the invention are known from the priorart. Suitable propellant gases are selected from among hydrocarbons suchas n-propane, n-butane or isobutane and halohydrocarbons such aspreferably fluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The propellant gases mentioned above may beused on their own or in mixtures thereof. Particularly preferredpropellant gases are fluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

Propellant-Free Inhalable Solutions

The compounds of formula I according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH. Co-solvents and/or other excipients may be added to thepropellant-free inhalable solutions used for the purpose according tothe invention. Preferred co-solvents are those which contain hydroxylgroups or other polar groups, e.g. alcohols—particularly isopropylalcohol, glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art. For the treatment formsdescribed above, ready-to-use packs of a medicament for the treatment ofrespiratory complaints are provided, containing an enclosed descriptionincluding for example the words respiratory disease, COPD or asthma, apteridine and one or more combination partners selected from thosedescribed above.

EXPERIMENTAL PROCEDURES AND SYNTHETIC EXAMPLES List Of Abbreviations

-   ACN acetonitrile-   APCI atmospheric pressure chemical ionization (in MS)-   Ctrl control-   DAD diode array detector-   DMA N,N-dimethylacetamide′-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EI electron impact (in MS)-   ESI electrospray ionization (in MS)-   ex example-   GC/MS gas chromatography with mass spectrometric detection-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluoro-phosphate-   HPLC high performance liquid chromatography-   HPLC/MS coupled high performance liquid chromatography-mass    spectrometry-   min minutes-   MS mass spectrometry-   NMR nuclear magnetic resonance-   R_(t) retention time (in HPLC)-   sec secondary-   TBTU O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   tert tertiary-   TFA trifluoroacetic acid-   TLC thin-layer chromatography-   UV ultraviolet absorption

Analytical Methods HPLC Methods

Methods:

1A

-   -   Column: Sunfire MS-C8, 5 μm, 4.6×100 mm    -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;        -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).    -   Flow rate: 1500 μL/min    -   Gradient: A/B (95/5%) for 1 min then to A/B (5/95%) in 10 min        for 2 min.

1E

-   -   Column: Symmetry C8, 5 μm, 3×150 mm    -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;    -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).    -   Flow rate: 1200 μL/min    -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3        min

1E (Fusion)

-   -   Column: Synergy Fusion RP80A, 4 μm, 4.6×100 mm    -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;    -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).    -   Flow rate: 1200 μL/min    -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3        min

1E (Hydro)

-   -   Column: Synergy Hydro RP80A, 4 μm, 4.6×100 mm    -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;        -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).    -   Flow rate: 1200 μL/min    -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3        min

Equipment:

-   -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,    -   Detection: UV @ 254 nm    -   Detection: Finnigan MSQ, quadrupole    -   Ion source: APCI

Method:

1F

-   -   Column: Xterra MS-C8, 3.5 μm, 4.6×50 mm    -   Mobile phase: A=(H₂O+0.1% TFA)+10% ACN; B=ACN    -   Flow rate: 1300 μL/min    -   Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min

1Fa

-   -   Column: Xterra MS-C18, 5 μm, 4.6×50 mm    -   Mobile phase: A=(H₂O+0.1% NH₄COOH)+10% ACN; B=ACN    -   Flow rate: 1300 μL/min    -   Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min

Equipment:

-   -   Instrument: HPLC/MS Waters. Hplc Alliance 2695 DAD, ZQ        Quadrupole    -   Detection: UV @ 254 nm    -   Detection: Waters ZQ, Quadrupole;    -   Ion source: ESI

Methods:

2A

-   -   Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;    -   Column Temperature: 40.0° C.    -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA    -   Flow rate: 1500 μL/min

Time A % B % Gradient: 0.00 95.00 5.00 2.00 0.00 100.00 2.49 0.00 100.002.50 95.00 5.00

2B

-   -   Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;    -   Column Temperature: 40.0° C.    -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA    -   Flow rate: 1000 μL/min

Time A % B % Gradient: 0.00 95.00 5.00 0.40 95.00 5.00 4.00 2.00 98.004.35 2.00 98.00 4.50 95.00 5.00

2C

-   -   Column: Sunfire C18 4.6×50 mm, 3.5 μm;    -   Column Temperature: 40.0° C.    -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA    -   Flow rate: 1500 μL/min

Time: A % B % Gradient: 0.00 95.00 5.00 2.00 0.00 100.00 2.49 0.00100.00 2.50 95.00 5.00

Equipment

-   -   Instrument: Waters ZQ2000 mass spectrometer    -   Detection: HP1100 HPLC+DAD (Wavelength range: 210 to 500        nM)+Gilson 215 Autosampler    -   Ion source: ESI+

Method:

2Ca

-   -   Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm    -   Mobile phase: A=water+0.1% HCOOH; B=ACN+0.1% HCOOH    -   Flow rate: 1.6 ml/min

A % B % Time [min] Gradient: 90 10 0.00 10 90 2.70 10 90 3.00 90 10 3.30

2Cb

-   -   Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm    -   Mobile: A=water+0.1% HCOOH; B=MeOH    -   Flow rate: 1.6 ml/min

A % B % Time [min] Gradient: 90 10 0.00 0 100 2.50 0 100 3.50

Equipment

-   -   Instrument: Agilent Technology; HP 1200 Series , DAD SL    -   Detection: UV 240-254 nm

Detection: Waters ZQ Single Quad

Ion source: ESI+

Method:

2F

-   -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm    -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN    -   B=ACN+10% (H₂O+0.1% HCOOH)    -   Flow rate: 1000 μL/min    -   Gradient: A/B (95/5%) for 1.5 min then to A/B (5/95%) in 10 min        for 1.5 min

2M

-   -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm    -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN        -   B=ACN+10% (H₂O+0.1% HCOOH)    -   Flow rate: 1200 μL/min    -   Gradient: A/B (90/10%) for 1.5 min then to A/B (5/95%) in 10 min        for 2 min

Equipment:

-   -   nstrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD, LCQDuo Ion        Trap    -   Detection: UV λ 254 nm    -   Detection: Finnigan LCQDuo Ion Trap    -   Ion source: ESI

Method:

2G

-   -   Eluent: A=H2O+0.05% TFA; B=ACN    -   Column: Waters SunFire C18 30×100 mm 5 μm

Gradient: slope 5%/min Initial: Flow = 40 mL/min % A = 80 % B = 20  8min Flow = 40 mL/min % A = 40 % B = 60  9 min Flow = 40 mL/min % A = 40% B = 60 10 min Flow = 40 mL/min % A = 5 % B = 95 11 min Flow = 40mL/min % A = 5 % B = 95 11.5 min   Flow = 40 mL/min % A = 80 % B = 20Stop run after 12 min Pre-run method: Initial condition for 3 min

Equipment:

Detector MS Waters ZQ: Detector DAD Waters 996: File: APrep_ESI.iprStart Wavelength: 210 nm Polarity: ESI+ End Wavelength: 600 nm Massrange: 130 to 900 amu Resolution: 1.2 nm Sampling rate: 1 spectra/secSample Manager mod Waters 2767: Make up pump mod Waters 515: Injectiontype: partial loop Flow = 1000 μL/min Injection Volume: set to OpenSolvent = ACN/Water/ Access Login mask Formic acid (90/10/0.1) Syringesize: 5000 uL Splitter: 1:1000 Trigger: mixed Total scan UV plus MS ALoop Volume: 5000 uL

Method:

2G a

-   -   Column: BEH C18, 1.8 um, 2.1×100 mm    -   Mobile phase: A=(H₂O+NH4COOH 0.1%)        -   B=ACN+10% H₂O    -   Flow rate: 450 μL/min    -   Gradient: 100% A for 1.5 min then to 100% B in 2.2 min

2 Gb

-   -   Column: BEH C18, 1.7 um, 2.1×50 mm    -   Mobile phase: A=H₂O 90%+0.1% TFA+10% ACN        -   B=ACN+10% H₂O    -   Flow rate: 480 μL/min    -   Gradient: A/B (90:10), then to A/B (10:90) in 1.2 minutes for        0.46 minute

Equipment:

-   -   Instrument: HPLC/MS AcquityWaters    -   Detection: UV λ 254 nm    -   Detection: Waters SQD, Quadrupole    -   Ion source: ESI

Method:

2H (Isocratic)

-   -   Column: DAICEL (IC) 5 μm, 4.6×250 mm    -   Mobile phase: A=(hexane+0.2% diethylamine); B=(MeOH/EtOH        50/50%).        -   A/B=50/50%    -   Flow rate: 1 ml/min

2I (Isocratic)

-   -   Column: DAICEL AS-H 5 μm, 4.6×250 mm    -   Mobile phase: A=Hexane ; B=EtOH (con AS-H), IPA (con AD-H)        -   A/B=98/2%    -   Flow rate: 1 ml/min

Equipment

-   -   Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD        Version A.    -   Detection: UV 220-300 nm

GC-MS Methods: Method:

3A

-   -   Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm    -   Carrier gas: Helium, 1 ml/min constant flow    -   Oven Program: 50° C. (hold 1 min.), to 100° C. in 10° C./min, to        200° C. in 20° C./min, to 300° C. in 30° C. /min

Equipment

-   -   Instrument: GC/MS Finnigan TRACE GC, TRACE MS quadrupole    -   Detection: TRACE MS quadrupole    -   Ion source: EI

Microwave Heating:

-   -   Discover® CEM instruments, equipped with 10 and 35 mL vessels.

Synthesis of Intermediates

Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dryethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyloxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture wasstirred under reflux overnight. The reaction mixture was cooled to roomtemperature and the precipitate formed was filtered, washed with ethanoland diethyl ether, dissolved in 200 ml of water and the solutionobtained acidified by a 37% aqueous solution of hydrochloric acid untilpH=2. The acidic aqueous solution was concentrated under vacuum and theresidue obtained was suspended and stirred in 100 ml of methanol. Theinsoluble inorganic salts were filtered off. The solution wasconcentrated. 15 g (97.4 mmol) of the desired compound were obtained.

was synthesized in analogy to Intermediate 1a, starting from acetamidinehydrochloride.

Potassium-tert-butylate (185.4 g, 1.65 mol) was dissolved in 650 ml ofdry ethanol and added slowly at −10° C. to a suspension of2-ethyl-3-oxo-succinic-acid diethyl ester (274.3 g, 1.27 mol) andformamidine acetate (171.4 g, 1.65 mol). The reaction mixture wasstirred at room temperature overnight, concentrated in vacuum and icewater was added. The mixture was acidified by a 37% aqueous solution ofhydrochloric acid until pH=5 and extracted with chloroform. After dryingthe organic layer, evaporation of the solvent in vacuum andcrystallization from ethyl acetate/hexane (2:3) gave 38 g (0.19 mol) ofthe desired compound.

A suspension of sodium tert-butoxide (3.9 g, 40.5 mmol) in 25 ml dryethanol was added to a solution of diethyl oxalpropionate (3.0 ml, 16.2mmol) and O-methylisourea hydrochloride (2.15 g, 19.5 mmol) in 25 ml dryethanol and the reaction mixture was refluxed for 18 h. The reactionmixture was allowed to cool to room temperature and the precipitateremoved by filtration. The filtrate was concentrated in vacuum, and theresidue was purified by reversed phase HPLC to give the desired product(752 mg, 3.5 mmol).

Intermediate 1d (550 mg, 2.6 mmol) was dissolved in a 4 M aqueoussolution of sodium hydroxide (3.0 ml, 12.0 mmol) and stirred for 3 h atroom temperature. The reaction mixture was acidified with concentratedhydrochloric acid to yield the desired product as precipitate (443 mg,2.4 mmol).

Intermediate 1a (7.0 g, 45.4 mmol) was suspended in 35 ml of thionylchloride (0.45 mol), 0.10 ml of DMF was added and the reaction mixturewas refluxed for 1 h. The reaction mixture was concentrated in vacuum.8.6 g (45 mmol) of the desired product were obtained and used in thenext steps without further purification.

was synthesized in analogy to Intermediate 2a, starting fromIntermediate 1b.

was synthesized in analogy to Intermediate 2a, starting fromIntermediate 1e.

Potassium carbonate (43.34 g, 0.31 mol) was suspended in 350 ml of dryethanol. A solution of Intermediate 2a (20 g, 0.10 mol) in 10 ml ofdichloromethane was added slowly at 0° C. The reaction mixture wasallowed to reach room temperature and stirred for 1 h. Potassiumcarbonate was filtered off and the solvent was removed under vacuum. Thecrude product was purified by flash chromathography (BIOTAGE SP1; silicagel cartridge: 65i; eluent: dichloromethane/ethyl acetate=95/5%). 5.3 g(26 mmol) of the desired compound were obtained.

was synthesized in analogy to Intermediate 3a, starting fromIntermediate 2b.

Intermediate 1c (38 g, 0.19 mol) was added to a mixture ofphosphorpentachloride (40.3 g, 0.19 mol) in 240 ml ofphosphoroxychloride. The reaction mixture was refluxed until a clearsolution was observed. The reaction mixture was concentrated in vacuum.The crude product obtained was purified by destillation in vacuum. 12 g(94.5 mmol) of the desired compound were obtained and used in the nextsteps without further purification.

5-Bromo-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester (63 g, 0.26mol) was suspended in 140 ml of phosphoroxychloride.Phosphorpentachloride (54 g, 0.26 mmol) was added and the reactionmixture was refluxed 72 h. The reaction mixture was concentrated invacuum and the crude product was suspended and stirred in warmed-uphexane (50° C.); a precipitate was formed and filtered off. The filtratewas concentrated under vacuum to obtain 64 g (243 mmol) of the desiredproduct which was used in the next steps without further purification.

3-Phenylcyclohexanone (500 mg, 2.87 mmol) and1-isocyanomethanesulfonyl-4-methyl-benzene (750 mg, 3.84 mmol) in 10 mlof 1,2-dimethoxyethane were stirred at 0° C. A solution of potassiumtert-butoxide (650 mg, 5.79 mmol) in 10 ml of 1,2-dimethoxyethane and 20ml of tert-butanol was added dropwise and the reaction mixture wasallowed to reach room temperature and stirred overnight. The reactionmixture was diluted with diethyl ether and washed with ice water. Theorganic phase was separated, washed with brine, dried over sodiumsulfate and concentrated under vacuum. 439 mg (2.3 mmol) of the desiredproduct were obtained.

was synthesized in analogy to Intermediate 4a, starting from(R)-3-Phenylcyclohexanone.

GC/MS (method 3A) R_(t)=11.52 min and 11.68 min (diastereoisomericmixture)

[M]⁺=185

was synthesized in analogy to Intermediate 4a, starting from(S)-3-Phenylcyclohexanone.

GC/MS (method 3A) R_(t)=11.50 min and 11.65 min (diastereoisomericmixture)

[M]⁺=185

The following intermediates were synthesized in analogy to Intermediates4a.

Starting Inter- ketone mediate STRUCTURE 3-(4-Chloro- phenyl)-cyclohexanone 4d

3-(4-Fluoro- phenyl)- cyclohexanone 4e

3-(4-Methoxy- phenyl)- cyclohexanone 4f

3-(4-Methyl- phenyl)- cyclohexanone 4g

3-(3-Fluoro- phenyl)- cyclohexanone 4h

3-isopropyl- cyclohexanone 4i

3-(5-Methyl- furan-2-yl)- cyclohexanone 4j

3- Phenylcyclo- pentanone 4k

3-(4-Chloro- phenyl)- cyclopentanone 4l

3-(4-Fluoro- phenyl)- cyclopentanone 4m

Intermediate 4j (400 mg, 2.11 mmol) was purified by flash chromatography(Biotage SP1 cartridge 25 g; eluent: cyclohexane/ethyl acetate=99/1%).60 mg (0.22 mmol) of diastereoisomerically pure cis-intermediate waseluted as second fraction (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=9.62 min

[M]⁺=189

Intermediate 4n (120 mg, 4.22 mmol) was separated by chiralsemipreparative HPLC. 20 mg of enantiomerically pure intermediate 4owere obtained (absolute stereochemistry unknown).

Chiral HPLC (method 2I (isocratic)) R_(t)=6.94 min

Further elution of the column gave 20 mg of enantiomerically pureintermediate 4p (absolute stereochemistry unknown).

Chiral HPLC (method 2I (isocratic)) R_(t)=7.27

Intermediate 4b (2.1 g, 11.28 mmol) was stirred under reflux in 20 ml of96% sulfuric acid and 20 ml of water overnight. The reaction mixture wascooled, treated with a 30% aqueous solution of sodium hydroxide and iceand washed with dichloromethane. The basic water phase was treated with37% aqueous solution of hydrochloric acid. The acidic aqueous solutionwas extracted with dichloromethane. The organic phase was washed withbrine, dried over sodium sulfate and concentrated under vacuum. 1.85 g(9.1 mmol) of the desired compound were obtained as a diastereoisomericmixture and used in the next steps without further purification.

Intermediate 5 (1.85 g, 9.06 mmol, mixture of 2 diastereomers) andtriethylamine (2.02 ml, 14 mmol) were stirred at 0° C. in 10 ml oftetrahydrofuran. A solution of ethylchloroformate (1.29 ml, 13.58 mmol)in 5 ml of tetrahydrofuran was added dropwise and the reaction mixturewas stirred at 0° C. for 1 h. Then, 10 ml of a 30% aqueous solution ofammonium hydroxide were added dropwise and the reaction mixture wasallowed to reach room temperature and stirred overnight. The reactionmixture was concentrated under vacuum, dissolved with dichloromethane,washed with a 1M aqueous solution of sodium hydroxide, washed withbrine, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by flash chromatography (Isolute silicacartridge 70 g; eluent: dichloromethane/methanol=99/1%). 145 mg (0.71mmol) of diastereoisomerically pure(1R,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relativestereochemistry assigned by NMR) were obtained.

GC/MS (method 3A) R_(t)=12.88 min

[M]⁺=203

Further elution of the column gave 230 mg (1.13 mmol) of thediastereoisomerically pure (1S,3R)-3-phenyl-cyclohexanecarboxylic acidamide (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=203

Intermediate 4c (300 mg, 1.61 mmol) was stirred under reflux in 2 ml of96% sulfuric acid and 2 ml of water for 3 h. The reaction mixture wascooled, treated with a 30% aqueous solution of sodium hydroxide and iceand washed with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by flash chromatography (Isolute silica cartridge20 g; eluent: dichloromethane/methanol=99/1%). 37 mg (0.18 mmol) of thediastereomerically pure (1S,3S)-3-phenyl-cyclohexanecarboxylic acidamide were obtained (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=12.88 min

[M]⁺=203

Further elution of the column gave 40 mg of the diastereomerically pure(1R,3S)-3-phenyl-cyclohexanecarboxylic acid amide (0.2 mmol) (relativestereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=203

5-Bromo-3-furan carboxylic acid (1.0 g, 5.23 mmol), phenylboronic acid(0.77 g, 6.28 mmol), tetrakis(triphenylphosphine)palladium(0) (1.21 g,1.04 mmol) and a 2M solution of sodium carbonate (6.28 ml, 12.57 mmol)were dissolved in 12 ml of 1,2-dimethoxy-ethane and the reaction mixturewas stirred under nitrogen atmosphere at 80° C. for 18 h. The reactionmixture was cooled to room temperature, diluted with dichloromethane andtreated with a 1M aqueous solution of hydrochloric acid until pH 1. Theorganic phase was separated, dried over sodium sulphate and concentratedunder vacuum. The carboxylic acid was obtained and used without furtherpurification for the synthesis of intermediate 6e in analogy tointermediate 6a.

Intermediate 6f was synthesized in analogy to intermediate 6a, startingfrom trans 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared asdescribed in literature for the preparation of trans3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.;Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of theAmerican Chemical Society; 1985, 107, 7247-7257).

Intermediate 6g was synthesized in analogy to Intermediate 6a, startingfrom cis 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared asdescribed in literature for the preparation of cis3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.;Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of theAmerican Chemical Society; 1985, 107, 7247-7257).

Intermediate 4a (390 mg, 2.10 mmol) and Raney-Nickel (10 mg) in 10 ml of1M solution of ammonia in ethanol was stirred under a hydrogenatmosphere (4 bar) overnight. The reaction mixture was filtered on acelite pad and concentrated under vacuum. The crude product was purifiedby flash chromatography (dichloromethane/methanol/NH₃(30% aqueoussolution)=95/5/0.1%) to obtain 217 mg (1.15 mmol) of the desiredproduct.

2.85 ml of a 1M solution of lithium aluminium hydride (2.85 mmol) intetrahydrofuran was dissolved in 10 ml of tetrahydrofuran and stirred at0° C. under nitrogen atmosphere. Intermediate 6a (145 mg, 0.71 mmol) in10 ml of tetrahydrofuran was added dropwise. The reaction mixture wasstirred at 0° C. for 2 h and then quenched with water and ice. Thereaction mixture was extracted with dichlorometane. The organic phasewas washed with a 1M aqueous solution of sodium hydroxide, brine, driedover sodium sulfate and concentrated under vacuum. 100 mg (0.55 mmol) ofthe desired product were obtained.

GC/MS (method 3A) R_(t)=11.53 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting fromIntermediate 6b.

GC/MS (method 3A) R_(t)=11.47 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting fromIntermediate 6c.

GC/MS (method 3A) R_(t)=11.53 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting fromIntermediate 6d.

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=189

The following intermediates were synthesised in atalogy to Intermediate7a.

Starting Inter- Inter- mediate mediate STRUCTURE 4d 7f

4e 7g

4f 7h

4g 7i

4h 7j

4i 7k

4k 7l

4l 7m

4m 7n

4n 7o

4o 7p

4p 7q

was synthesized in analogy to intermediate 7b, starting fromintermediate 6e.

was synthesized in analogy to intermediate 7b, starting fromintermediate 6f.

was obtained and isolated as side product in the preparation ofIntermediate 7s

was synthesized in analogy to Intermediate 7b, starting fromIntermediate 6g.

was obtained and isolated as side product in the preparation ofIntermediate 7u.

Tris(dibenzylideneacetone)dipalladium (1.71 g, 1.87 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (2.32 g, 3.72 mmol) werestirred in 30 ml of toluene for 10 min under argon athmosphere.

Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (2 g, 9.33 mmol),bromobenzene (1.27 ml, 0.01 mol) and sodium tert-butoxide (1.43 g, 14.93mmol) were added and the reaction mixture was stirred under refluxovernight. The reaction mixture was concentrated under vacuum, the crudeproduct was dissolved in dichlorometane and the organic phase wasfiltered on a celite pad. The organic phase was washed with an aqueoussaturated sodium carbonate solution, with brine, dried over sodiumsulfate, concentrated under vacuum. The crude product obtained wasdissolved in methanol and loaded onto a SCX cartridge (25 g). Afterwashing with methanol the product was eluted with a 2M solution ofammonia in methanol. 1.17 g (4.03 mmol) of the desired product wereobtained and used in next steps without any other purification.

To a solution of Intermediate 8a (1.1 g, 3.79 mmol) in 10 ml of1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (15 ml,60 mmol) was added dropwise; the reaction mixture was stirred at roomtemperature overnight before being concentrated under vacuum. The crudeproduct was purified by flash chromatography (Isolute silica gelcartride: 50 g; eluent: dichloromethane/methanol=95/5%). 250 mg (1.31mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates8a and 9a.

Starting Starting Inter- Inter- amine bromide mediate STRUCTURE mediateSTRUCTURE (S)-1- Pyrrolidin-3- ylmethyl- carbamic acid tert- butyl esterbromo- benzene 8b

9b

(R)-1- Pyrrolidin-3- ylmethyl- carbamic acid tert- butyl ester bromo-benzene 8c

9c

Piperidine-3- yl-methyl- carbamic acid tert- butyl ester 1-bromo-4-trifluoro methyl- benzene 8d

9d

Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (100 mg, 0.47mmol), 2-chloro-4-fluoro-benzonitrile (72.5 mg, 0.47 mmol) andN,N-diisopropylethylamine (0.160 ml, 1.23 mmol) were dissolved in 10 mlof DMF and the reaction mixture was stirred at 125° C. overnight. Thereaction mixture was concentrated under vacuum and the crude product waspurified by flash chromatography (Isolute silica gel cartride: 5 g;eluent: ethyl acetate). 125 mg (0.36 mmol) of the desired compound wereobtained.

To a solution of Intermediate 10 (125 mg, 0.36 mmol) in 5 ml of1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (0.12 ml,480 mmol) was added dropwise; the reaction mixture was stirred at roomtemperature overnight before being concentrated under vacuum. 102 mg(0.36 mmol) of the desired compound were obtained.

A solution of 4-methanesulfonylamino-piperidine-1-carboxylic acidtert-butyl ester (500 mg; 1.79 mmol) in 5 ml of acetonitrile was cooledto −5° C., iodoethane (308 mg, 1.79 mmol) and sodium hydride (96 mg,3.59 mmol) were added; the reaction mixture was allowed to warm to roomtemperature and stirred for 72 h.

The reaction mixture was concentrated under vacuum; the residue wasdissolved in ethyl acetate and washed with an aqueous saturated sodiumbicarbonate solution and then with water.

The organic phase was dried over sodium sulfate, filtered andconcentrated under vacuum. The crude product was purified by flashchromatography (Isolute silica gel cartridge: 10 g, eluent:dichloromethane) to obtain 332 mg (1.1 mmol) of the desired compound.

To a solution of intermediate 12 (330 mg, 1.1 mmol) in 20 ml of1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (4.06 ml,16 mmol) was added dropwise; the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum to obtain 262 mg (1.1 mmol) of the desired compound.

trans-4-Azido-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester(1.6 g, 6.24 mmol), Pd/C 10% (200 mg) and acetic acid (1.6 ml) weredissolved in 25 ml of methanol and the reaction mixture was stirredunder hydrogen atmosphere (4 bar) for 3 h. The reaction mixture wasfiltered on a celite pad and concentrated under vacuum. The crudeproduct was purified by flash chromatography (Biotage SP1 cartridge 65i,eluent: dichloromethane/methanol=95/5%). 900 mg (3.91 mol) of thedesired compound were obtained.

Intermediate 14 (900 mg, 3.91 mmol) and N,N-diisopropylethylamine (0.86ml, 5 mmol) were dissolved in 25 ml of dichloromethane. The reactionmixture was cooled to 0° C. and methanesulfonylchloride (0.33 ml, 4.30mmol) was added. The reaction mixture was stirred at 0° C. for 20 min,then, water was added. The organic phase was separated, washed with anaqueous saturated sodium bicarbonate solution, dried over sodium sulfateand concentrated under vacuum. The crude product was purified by flashchromatography (Isolute silica cartridge: 10 g, eluent: hexane/ethylacetate=50/50%). 170 mg (0.55 mol) of the desired compound wereobtained.

Intermediate 15a (350 mg, 1.13 mmol) and potassium carbonate (157 mg,1.13 mmol) were dissolved and stirred in 15 ml of acetonitrile. Asolution of iodomethane (0.071 ml, 1.13 mmol) in 5 ml of acetonitrilewas added dropwise and the reaction mixture was warmed to 60° C.overnight. The reaction mixture was concentrated under vacuum and thecrude product was dissolved in ethyl acetate. The organic phase waswashed with an aqueous saturated sodium bicarbonate solution, separated,dried over sodium sulfate and concentrated under vacuum. 300 mg (0.93mmol) of the desired compound were obtained and used in the next stepswithout further purification.

Intermediate 15a (170 mg, 0.55 mmol) in 2 ml of 1,4-dioxane was stirredat 10° C. A 4M solution of hydrochloric acid in 1,4-dioxane (8 ml, 32mmol) was added dropwise and the reaction mixture was stirred at roomtemperature for 5 h. The reaction mixture was concentrated under vacuumto obtain 115 mg (0.55 mmol) of the desired compound.

was synthesized in analogy to Intermediate 16a, starting fromIntermediate 15b.

was synthesized in analogy to Intermediate 15a, starting from(3S,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester.

Intermediate 17 (660 mg, 2.14 mmol) in 10 ml of 1,4-dioxane was stirredat 10° C. Trifluoroacetic acid (2 ml, 26 mmol) was added dropwise andthe reaction mixture was stirred at room temperature 18 h. The reactionmixture was concentrated under vacuum to obtain 600 mg (1.86 mmol) ofthe desired compound, used in the next step without furtherpurification.

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11 g, 47.91mmol) was suspended in 200 ml of 1,2-dichloroethane,N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol) were addedand the reaction mixture was stirred at room temperature for 30 min.Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was added and thereaction mixture was stirred at room temperature for 72 h. The reactionmixture was diluted with dichloromethane and washed with an aqueoussaturated sodium bicarbonate solution.

The organic phase was dried over sodium sulfate and concentrated undervacuum. The crude product was purified by flash chromatography (BiotageSP1; silica gel cartridge: 65i; eluent: ethyl acetate/methanol=50/50%)to obtain 7.2 g (19.2 mmol) of the desired compound.

Intermediate 19a (7.2 g, 19.2 mmol) was suspended in 20 ml of1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192 mmol) in1,4-dioxane was added dropwise. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum. 6.3 g (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates19a and 20a.

Carba- mate Diamino Starting Starting Inter- Inter- ketone amine mediateSTRUCTURE mediate STRUCTURE 1-(tert- butoxy- carbonyl)- 4-oxo-piperidine Ethane- sulfonic acid methyl- piperi- din-4-yl- amide 19b

20b

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (R)-N- Pyrrol- idin-3- yl-methane sulfona- mide 19c

20c

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (S)-N- Pyrrol- idin-3- yl-methane sulfona- mide 19d

20d

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine Ethane- sulfonic acidpiperi- din-4-yl- amide 19e

20e

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine Piperi- dine-4- carbox-ylic acid methyl amide 19f

20f

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine Piperi- dine-4- sulfo-nicacid methyl amide 19g

20g

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (R)- Pyrrol- idine-3-carbox- ilic acid methyl- amide 19h

20h

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (S)- Pyrrol- idine-3-carbox- ilic acid methyl- amide 19i

20i

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (S)- Pyrrol- idine-3-carbox- ilic acid amide 19j

20j

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine 16a 19k

20k

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine (R)- Pyrrol- idine-3-carbox- ilic acid amide 19l

20l

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine 47b 19lf

20lf

1-(tert- butoxy- carbonyl)- 4-oxo- piperidine 47c 19lg

20lg

4-Methylamino-piperidine-1-carboxylic acid tert-butyl ester (500 mg,1.87 mmol) was suspended in 10 ml of 1,2-dichloroethane.Tetrahydro-pyran-4-one (0.17 ml, 1.87 mmol) was added and the reactionmixture was stirred at room temperature for 30 min. Sodiumtriacetoxyborohydride (593 mg, 2.80 mol) was added and the reactionmixture was stirred for 18 h. The reaction mixture was diluted withdichloromethane and washed with an aqueous saturated sodium bicarbonatesolution.

The organic phase was dried over sodium sulfate and concentrated undervacuum. The crude product was purified by flash chromatography (Isolutesilica gel cartridge 10 g; eluent: dichloromethane/methanol=94/6%). 240mg (0.80 mmol) of the desired compound were obtained.

Intermediate 191a (240 mg, 0.80 mmol) was suspended in 10 ml of1,4-dioxane, a 4M solution of hydrochloric acid (2.0 ml, 8.0 mmol) in1,4-dioxane was added dropwise. The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was concentrated undervacuum. 200 mg (0.74 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates191a and 201a

Carba- mate Amino Starting Starting Inter- Inter- amine ketone mediateSTRUCTURE mediate STRUCTURE 4- Methyl- amino- piperi- dine-1- carb-oxylic acid tert- butyl ester 3- Methoxy- tetrahy- dro-pyran- 4-one 19lb

20lb

4- Methyl- amino- piperi- dine-1- carb- oxylic acid tert- butyl ester2,6- dimethyl- tetra- hydro- pyran-4- one 19lc

20lc

4- Methyl- amino- piperi- dine-1- carb- oxylic acid tert- butyl ester4,4- difluoro- cyclo- hexa- none 19ld

20ld

4- amino- piperi- dine-1- carb- oxylic acid tert- butyl ester 3-Methoxy- tetrahy- dro-pyran- 4-one 19le

20le

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (1.13 g, 4.95mmol) was suspended in 10 ml of 1,2-dichloroethane,N,N-diisopropylethylamine (2.6 ml, 14.9 mmol) andN-carbethoxy-3-methoxy-piperidin-4-one (1 g, 4.95 mmol) were added andthe reaction mixture was stirred at room temperature for 30 min. Sodiumtriacetoxyborohydride (3.16 g, 14.85 mol) was added and the reactionmixture was stirred at room temperature for 72 h. The reaction mixturewas diluted with dichloromethane and washed with an aqueous saturatedsodium bicarbonate solution.

The organic phase was dried over sodium sulfate and concentrated undervacuum. 1.5 g (3.97 mmol) of the desired compound were obtained and usedwithout further purification.

Intermediate 19m (1.5 g, 3.97 mmol) and potassion hydroxide (4.46 g,7.94 mmol) were suspended in 25 ml of ethanol and the reaction mixturewas stirred under reflux overnight.

The reaction mixture was concentrated under vacuum and the crude productwas loaded on a SCX cartridge (25 g) and eluted with a 2M solution ofammonia in methanol. 1.2 g (3.97 mmol) of the desired compound wereobtained.

Piperidin-4-yl-carbamic acid tert-butyl ester (6 g, 30 mmol) and1-(benzyloxycarbonyl)-4-oxopiperidine (9.6 g, 48 mmol) were dissolved in50 ml of dichloromethane and the reaction mixture was stirred at roomtemperature for 30 min; sodium triacetoxyborohydride (12.23 g, 57.5mmol) was added and the reaction mixture was stirred at room temperatureovernight.

The reaction mixture was diluted with dichloromethane and washed with anaqueous saturated sodium bicarbonate solution. The organic phase wasdried over sodium sulfate and concentrated under vacuum. The crudeproduct was treated with acetone/isopropyl ether and the precipitateobtained was filtered off 8.4 g (20 mmol) of the desired product wereobtained.

To a solution of intermediate 21 (8.4 g, 20 mmol) in 150 ml of1,4-dioxane previously cooled to 0° C., 12.6 ml (50 mmol) of a 4Msolution of hydrochloric acid in 1,4-dioxane were added dropwise; thereaction mixture was allowed to warm to room temperature and was stirredat that temperature overnight. The solid precipitated from the reactionmixture was filtered off and dried at 50° C. under vacuum to obtain 6 g(15 mmol) of the desired compound.

Intermediate 22 (6.0 g, 15 mmol) was suspended in 55 ml ofdichloromethane; triethylamine (6.43 ml, 46 mmol) was added and thereaction mixture was cooled to 0° C. and stirred at that temperature for30 min. Methanesulfonyl chloride (1.43 ml, 18 mmol) in 5 ml ofdichloromethane was added dropwise. The reaction mixture was stirred at0° C. for 1 h; then water was added and the reaction mixture wasextracted with dichloromethane. The organic phase was washed with anaqueous saturated sodium bicarbonate solution, with brine, dried oversodium sulfate and concentrated under vacuum. The crude product wastreated with diisopropyl ether, the precipitate was filtered off anddried. 5 g (13 mmol) of the desired product were obtained.

Intermediate 23 (5 g, 13 mmol) was dissolved in 50 ml of methanol;acetic acid (1.5 ml, 25.3 mmol) and Pd/C 10% (500 mg) were added insequence and the reaction mixture was stirred under a hydrogenatmosphere (3 bar) at room temperature for 5 days. The reaction mixturewas filtered on a celite pad and the organic phase was loaded on a SCXcartridge (10 g). After washing with methanol, the desired compound waseluted with a 2M solution of ammonia in methanol. 3.7 g (4.6 mmol) ofthe title compound were obtained.

Intermediate 24 (1.1 g, 4.21 mmol) was suspended in 20 ml of drydichloromethane, N,N-diisopropylethylamine (1.47 ml, 8.42 mmol) and DMF(137 μl, 1.67 mmol) were added and the reaction mixture was stirredunder nitrogen atmosphere and cooled to 0° C. Intermediate 2a (812 mg,4.21 mmol) in 5 ml of dichloromethane was added dropwise and thereaction mixture was allowed to warm up to room temperature and stirredfor 1.5 h; the reaction mixture was diluted with dichloromethane andwashed with an aqueous saturated sodium bicarbonate solution. Theorganic phase was separated, dried over sodium sulfate and concentratedunder vacuum. The crude product was purified by flash chromatography(isolute silica gel cartridge: 10 g; eluent:dichloromethane/methanol=95/5%). 1.0 g (2.41 mmol) of the title compoundwere obtained.

The following intermediates were synthesized in analogy to Intermediate25a.

Chloro- Piper- pyrim- Core idine idine Inter- Inter- Inter- mediatemediate mediate STRUCTURE 2a 20a 25b

2a 20b 25c

2a 20f 25d

2a 20h 25e

2a [1,4']-Bi- piperidinyl- 4-ol 25f

2a 4-Methoxy- [1,4']bi- piperidinyl 25g

2a 4-Piperidin- 4-yl-morpho- line 25h

2a [1,4']Bi- piperidinyl 25i

2a [1,4']-Bi- piperidinyl- 3-ol 25j

2b 24 25k

2b 20a 25l

2b [1,4']-Bi- piperidinyl- 4-ol 25m

2c 20a 25n

2a 20le 25o

Intermediate 3a (10 g, 49.35 mmol) and N,N-diisopropylethylamine (17 ml,99 mmol) were dissolved in 20 ml of dry DMF;2-(3,4-dichloro-phenyl)-ethylamine (9.57 g, 49.35 mmol) in 10 ml of dryDMF was added and the reaction mixture was stirred at 90° C. for 2 h.The reaction mixture was cooled to room temperature, water was added andthe reaction mixture was extracted with dichloromethane; the organicphase was concentrated under vacuum, the crude product was suspended andstirred in diethyl ether and the precipitate was filtered off and dried.10.2 g (28.8 mmol) of the desired compound were obtained.

Intermediate 26a (10.0 g, 28.25 mmol) was dissolved in 70 ml of ethanoland a solution of LiOH (3.52 g, 83.88 mmol) in 70 ml of water was added.The reaction mixture was stirred at 70° C. for 1 hour, concentratedunder vacuum and the remaining aqueous solution was acidified by 20 mlof 4M solution of hydrochloric acid in 1,4-dioxane; the precipitateformed was filtered off and dried. 8.6 g (26.37 mmol) of the desiredproduct were obtained.

The following intermediates were synthesized in analogy to Intermediates26a and 27a.

Ester Acid Core- Inter- Inter- Inter- medi- medi- mediate Amine ateSTRUCTURE ate STRUCTURE 3a 3,4- Dichloro- benzyl- amine 26b

27b

3a 4-tert-butyl- benzyl- amine 26c

27c

3a biphenyl-3- ylmethan- amine 26d

27d

3b 4-tert-butyl- benzyl- amine 26e

27e

3c 2-(3,4- dichloro- phenyl)- ethylamine 26f

27f

3c biphenyl-3- yl-methan- amine 26g

27g

3d biphenyl-3- yl-methan- amine 26h

27h

3a Inter- mediate 7c 26ha

27ha

3d Inter- mediate 7c 26hb

27hb

3a Inter- mediate 7p 26hc

27hc

3a Inter- mediate 7q 26hd

27hd

3a Inter- mediate 7t 26he

27he

3a Inter- mediate 7v 26hf

27hf

3b Inter- mediate 7t 26hr

27hr

3b Inter- mediate 7v 26hs

27hs

Intermediate 3d (2 g, 7.53 mmol) and N,N-diisopropylethylamine (1.97 ml,11.3 mmol) were dissolved in 15 ml of dry DMF; 4-tertbutyl-benzylamine(1.6 ml, 9.04 mmol) was added and the reaction mixture was stirred at60° C. for 18 h. The reaction mixture was cooled to room temperature,water was added and the reaction mixture was extracted withdichloromethane; the organic phase was concentrated under vacuum and thecrude product was purified by flash chromatography (BIOTAGE SP1; silicagel cartridge: 65i; eluent: hexane/ethyl acetate=70/30%). 1.5 g (3.82mmol) of the desired compound were obtained.

Intermediate 26hb (75 mg, 179 μmol), tributyl(vinyl)tin (200 μA, 685μmol) and bis(triphenylphosphine)palladium chloride (13 mg, 18 μmol)were added to 3 ml 1,2-dichloroethane. The reaction mixture was heatedin the microwave for 4 h at 120° C. Then, the solvent was removed invacuum and the residue was purified by reversed phase HPLC to give thedesired product (56 mg, 117 mmol).

was synthesized in analogy to intermediate 26ib, starting fromintermediate 26hb and tributyl(ethynyl)tin.

Intermediate 26i (500 mg, 1.27 mmol) and CuCN (114 mg, 1.27 mmol) weredissolved in 5 ml of DMA and the reaction mixture was stirred at 100° C.overnight. The reaction mixture was cooled, diluted with dichloromethaneand the organic phase was washed with water, dried over sodium sulfateand concentrated under vacuum. 30 mg (0.1 mmol) of the crude productwere obtained and used in the next step without purification.

was synthesized in analogy to 27a starting from intermediate 26ib.

was synthesized in analogy to 27a starting from intermediate 26ic.

Intermediate 27a (4 g, 12.14 mmol), TBTU (3.9 g, 12.14 mmol) andN,N-diisopropylethylamine (5.34 ml, 30.35 mmol) were dissolved in 25 mlof DMF. The reaction mixture was stirred under nitrogen atmosphere atroom temperature for 30 min; then piperidin-4-one hydrochloride (1.66 g,12.14 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum and the crude product was dissolved in dichloromethane. Theorganic phase was washed with a saturated aqueous solution of sodiumbicarbonate, with a 1M aqueous solution of sodium hydroxide, with brine,then dried over sodium sulfate, filtered and concentrated under vacuum.The crude product was purified by flash chromatography (BIOTAGE SP1;silica gel cartridge: 65i; eluent: dichloromethane/methanol=95/5%). 2.2g (5.4 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to intermediate28a.

Acid Inter- Inter- mediate Amine mediate STRUCTURE 27b Piperidin-4-one28b

27c Piperidin-4-one 28c

27d Piperidin-4-one 28d

27g Piperidin-4-one 28e

27c Azepan-4-one 28f

27e Piperidin-4-one 28g

Intermediate 28a (500 mg, 1.22 mmol), piperazine-1-carboxylic acidtert-butyl ester (228 mg, 1.23 mmol) and 2-picoline borane complex(131.3 mg, 1.22 mmol) in 15 ml of methanol were stirred at roomtemperature for 72 h; the reaction mixture was concentrated under vacuumand the crude product was dissolved in dichloromethane. The organicphase was washed with water, dried over sodium sulfate, filtered andconcentrated under vacuum. The crude product was purified by flashchromatography (Isolute silica gel cartridge: 20 g; eluent:dichloromethane/methanol=98/2%). 280 mg (0.48 mmol) of the desiredcompound were obtained.

Intermediate 29 (280 mg, 0.48 mmol) was dissolved in 6 ml of1,4-dioxane; 4 ml (16 mmol) of a 4M solution of hydrochloric acid in1,4-dioxane were added dropwise and the reaction mixture was stirred atroom temperature overnight. The solvent was concentrated under vacuum.240 mg (0.46 mmol) of the desired compound were obtained.

Intermediate 27c (500 mg, 1.67 mmol), TBTU (643 mg, 2 mmol) andN,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were dissolved in 5 ml ofDMF. The reaction mixture was stirred under nitrogen atmosphere at roomtemperature for 10 min; then[1,4]diazepan-1-carboxylic acid tert-butylester (334 mg, 1.67 mmol) was added and the reaction mixture was stirredat room temperature overnight. The reaction mixture was diluted withdichloromethane and washed with an aqueous saturated solution of sodiumbicarbonate. The organic phase was separated, dried over sodium sulfateand concentrated under vacuum. The crude product was suspended indiisopropyl ether and stirred, the solid obtained was filtered anddried. 700 mg (1.45 mmol) of the desired compound were obtained.

Intermediate 31 (600 mg; 1.24 mmol) was suspended in 5 ml of diethylether, 5 ml of a 1M solution of hydrochloric acid in diethyl ether wasadded dropwise and the reaction mixture was stirred at room temperatureovernight. The solvent was concentrated under vacuum and the crudeproduct was loaded on a SCX cartridge (10 g) and eluted with a 2Msolution of ammonia in methanol. 470 mg (1.23 mmol) of the titlecompound were obtained.

Intermediate 3a (1.5 g, 7.47 mmol) andtetrakis(triphenylphosphine)palladium (143.9 mg, 0.12 mmol) weresuspended in 40 ml of toluene under nitrogen atmosphere;4-tert-butyl-benzylzinc bromide (29.9 ml, 15 mmol) was added dropwiseand then the reaction mixture was stirred at 20° C. for 8 h. 5 ml ofmethanol, 40 ml of water and 100 ml of dichloromethane were added. Theorganic phase was separated, dried over sodium sulfate and concentratedunder vacuum. The crude product obtained was purified by flashchromatography (Biotage column 40M+; eluent: dichloromethane/ethylacetate=95/5%). 230 mg (0.74 mmol) of the desired compound wereobtained.

To a solution of 4-tert-butylphenylacetylene (5 ml, 28 mmol) in 20 ml ofdry tetrahydrofuran under nitrogen atmosphere, a solution ofcatecholborane (3.41 ml, 31 mmol) in 20 ml of dry tetrahydrofuran wasadded dropwise. The reaction mixture was refluxed for 2 h and thenconcentrated under vacuum; the crude product obtained was dissolved inethyl acetate and the organic phase was washed with a 2 M aqueoussolution of hydrochloric acid. The organic phase was separated, washedwith brine, dried over sodium sulfate and concentrated under vacuum. Thecrude product obtained was purified by flash chromatography (Biotagecolumn 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.82mmol) of the desired compound were obtained.

Intermediate 3a (600 mg, 3 mmol), intermediate 34 andtetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) were dissolvedin 3.6 ml of a 2 M aqueous solution of sodium carbonate and 40 ml of 1,2dimethoxyethane. The reaction mixture was stirred at 80° C. overnight.Water was added and the reaction mixture was extracted withdichloromethane. The organic phase was separated, dried over sodiumsulfate and concentrated under vacuum. The crude product obtained waspurified by flash chromatography (Biotage column 40M+; eluent:dichloromethane/ethyl acetate=95/5%). 550 mg (1.60 mmol) of the desiredcompound were obtained.

Intermediate 35 (250 mg, 0.77 mmol) was dissolved in 5 ml of ethanol and5 ml of tetrahydrofuran. Pd/C (35 mg) was added and the reaction mixturewas stirred under hydrogen atmosphere (1 atm) at room temperatureovernight. The reaction mixture was filtered on a celite pad andconcentrated under vacuum. 170 mg (0.52 mmol) of the desired compoundwere obtained.

Palladium acetate (170 mg, 0.75 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (936 mg, 1.5 mmol) weredissolved in 25 ml of 1,4-dioxane and stirred at 40° C. for 30 minutes.2-chloro-3-methylpyridine-4-carboxylic acid ethyl ester (500 mg, 2.5mmol), 3,4-dichlorobenzylamine (680 mg, 5 mmol) and cesium carbonate(715.5 mg, 3.76 mmol) were added and the reaction mixture was refluxedfor 48 h. The solvent was concentrated under vacuum and the crudeproduct was loaded on a SCX cartridge (10 g) and eluted with a 2Msolution of ammonia in methanol. The solvent was concentrated undervacuum and the crude product obtained was purified by flashchromatography (Biotage column 25M+; eluent: ethyl acetate). 250 mg(0.73 mmol) of the desired compound were obtained.

3-(Bromomethyl)biphenyl (150 mg, 0.58 mmol), sodium carbonate (188 mg,1.75 mmol) and 3-amino-2-methyl-benzoic acid ethyl ester (0.1 ml, 0.58mmol) were mixed in 2 ml of DMF and stirred at 100° C. for 2 hours. Thesolvent was then concentrated under vacuum and the crude product waspurified by reverse phase preparative HPLC. 131 mg (0.37 mmol) of thedesired compound were obtained.

Intermediate 35 (300 mg, 0.92 mmol) was dissolved in 4 ml of ethanol and4 ml of water. Lithium hydroxide (194 mg, 4.7 mmol) was added and thereaction mixture was stirred at 70° C. for 2 h, concentrated undervacuum and the remaining aqueous solution was acidified by 10 ml of a 4Msolution of hydrochloric acid in 1,4-dioxane and extracted withdichloromethane; the organic phase was separated, washed with brine,dried over sodium sulfate and concentrated under vacuum. 250 mg (0.84mmol) of the desired product were obtained.

The following intermediates were synthesized in analogy to intermediate39a

Ester Acid Inter- Inter- medi- medi- ate ate STRUCTURE 33 39b

36 39c

37 39d

38 39e

Intermediate 27c (660 mg, 2.20 mmol), TBTU (849 mg, 2.65 mmol) andN,N-diisopropylethylamine (0.57 ml, 3.31 mmol) were dissolved in 25 mlDMF. The reaction mixture was stirred under nitrogen atmosphere at roomtemperature for 10 min; then piperidin 4-yl carbamic acid tert-butylester (441 mg, 2.20 mmol) was added and the reaction mixture was stirredat room temperature for 18 h. The reaction mixture was diluted withdichloromethane and washed with an aqueous saturated solution of sodiumbicarbonate. The organic phase was separated, dried over sodium sulfateand concentrated under vacuum. The crude product was purified by flashchromatography (Biotage SNAP column 50 g; eluent:dichloromethane/methanol=90/10%). 990 mg (2.05 mmol) of the desiredcompound were obtained.

Intermediate 40a (990 mg, 2.05 mmol) was suspended in 50 ml of1,4-dioxane, a 4M solution of hydrochloric acid (8.5 ml, 34 mmol) in1,4-dioxane was added dropwise. The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was concentrated undervacuum. 780 mg (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates40a and 41a.

Carba- mate Amine Starting Starting Inter- Inter- acid amine mediateSTRUCTURE mediate STRUCTURE Inter- mediate 27ha piperidin 4-yl carbamicacid tert- butyl ester 40b

41b

4,4-Difluorocyclohexanone (500 mg, 3.73 mmol) and potassium hydroxide(502 mg, 8.95 mmol) were disoolved in 10 ml of methanol. The reactionmixture was cooled to 0° C. and a solution of iodine (1.04 g, 4.10 mmol)in 20 ml of methanol was added dropwise within 1 h. The reaction mixturewas stirred at room temperature for 18 h, and then concentrated undervacuum. The crude product was stirred in 10 ml of dichlorometane and theprecipitate was filtered off. The filtrate was concentrated under vacuumand 480 mg of the desired product (2.45 mmol) were obtained as an oil.

Sodium hydride (196 mg, 4.89 mmol) was suspended in 10 ml oftetrahydrofurane. The reaction mixture was cooled to 0° C. and asolution of Intermediate 42 (480 mg, 4.45 mmol) in 5 ml oftetrahydrofurane was added dropwise. The reaction mixture was stirred at0° C. for 1 h, then iodomethane (0.305 ml, 4.89 mmol) was added. Thereaction mixture was stirred at room temperature for 4 h. 0.1 ml of a37% aqueous solution of hydrochloric acid and 0.1 ml of water wereadded, then additional 0.3 ml of a 37% aqueous solution of hydrochloricacid were added. The reaction mixture was stirred at room temperaturefor 18 h. The reaction mixture was concentrated under vacuum and 400 mg(2.44 mmol) of the desired product were obtained as an oil.

Iodomethane (3.48 ml, 55.88 mmol) was dissolved in 250 ml oftetrahydrofurane, the reaction mixture was stirred at 0° C. undernitrogen atmosphere and sodium hydride (60% on mineral oil, 2.23 mg,5.88 mmol) was added. After 15 minutes, trans4-azido-tetrahydropyran-3-ol (4.0 g, 27.94 mmol) was added and thereaction mixture was allowed to reach room temperature and stirred for18 h. 50 ml of water were added, the organic phase was separated, driedover sodium sulphate and concentrated under vacuum. The crude oilobtained was purified by flash chromatography (Biotage SNAP column 100g; eluent: dichloromethane/ethyl acetate=80/20%). 200 mg (1.27 mmol) ofthe desired regioisomer were obtained as trans racemate (relativeconfiguration assigned by NMR).

Intermediate 44 (200 mg, 1.27 mmol) was dissolved in 250 ml of methanol,Pd/C (50 mg) was added and the reaction mixture was stirred underhydrogen atmosphere (4 bar) for 18 h. The reaction mixture was filteredon a celite pad and the organic phase was concentrated under vacuum. 110mg (0.84 mmol) of the desired product were obtained as trans racemate.

3-Methoxy-tetrahydro-pyran-4-one (500 mg, 3.84 mmol), benzylamine (0.42ml, 3.84 mmol) and Raney-Nickel (100 mg) were suspended in 20 ml of dryethanol and the reaction mixture was stirred under hydrogen atmosphere(4.5 bar) for 3 days. The reaction mixture was filtered on a celite padand the organic phase was concentrated under vacuum. The crude productobtained was dissolved in 10 ml of methanol, loaded on a SCX cartridge(10 g) and eluted with a 2M solution of ammonia in methanol. The solventwas concentrated under vacuum and the crude product obtained waspurified by flash chromatography (Isolute cartridge 10 g; eluent:dichloromethane/methanol=96/4%). 163 mg (0.73 mmol) of the desiredproduct were obtained as cis racemate (relative configuration assignedby NMR).

3-Methoxy-tetrahydro-pyran-4-one (1 g, 7.68 mmol),(R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) and Raney-Nickel (200mg) in 10 ml dry ethanol were stirred under a hydrogen atmosphere (5bar) for 15 days. The reaction mixture was diluted with 20 ml ofmethanol and 20 ml of tetrahydrofurane, stirred for 15 minutes, filteredon a celite pad and concentrated under vacuum. The crude product wasloaded on a SCX cartridge (50 g). The cartridge was washed with methanoland the desired product was eluted with a 7 M solution of ammonia inmethanol. The basic organic phase was concentrated under vacuum and thecrude product obtained was purified by flash chromatography(dichloromethane/methanol=98/2%) to obtain 710 mg (3.02 mmol) of thedesired product as single stereoisomer (diastereoisomeric purityconfirmed and relative cis stereochemistry assigned by NMR).

was synthesised in analogy to Intermediate 46b, starting from3-Methoxy-tetrahydro-pyran-4-one and (S)-(−)-1-phenylethylamine(diastereoisomeric purity confirmed and relative cis stereochemistryassigned by NMR).

Intermediate 46a (163 mg, 0.73 mmol) was dissolved in 10 ml of methanol,Pd/C (50 mg) was added and the reaction mixture was stirred underhydrogen atmosphere (4.5 bar) for 18 h. The reaction mixture wasfiltered on a celite pad and the organic phase was concentrated undervacuum. 80 mg (0.61 mmol) of the desired product were obtained as cisracemate.

Intermediate 46b (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and acetic acid(0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred under a hydrogenatmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20 mlof methanol, stirred for 15 minutes, filtered on a celite pad andconcentrated under vacuum. The crude product was loaded on a SCXcartridge (50 g). The cartridge was washed with methanol and the desiredproduct was eluted with a 7 M solution of ammonia in methanol. The basicorganic phase was concentrated under vacuum and 513 mg (3.91 mmol) ofthe desired product were obtained as single stereoisomer.

was synthesised in analogy to Intermediate 47b, starting fromIntermediate 46c

Intermediate 47b was stirred in diethyl ether and a 2M solution ofhydrochloric acid in diethyl ether was added drop-wise until a whitesolid was formed. The reaction mixture was concentrated under vacuum,the crude product was suspended in methanol and the reaction mixture wasconcentrated under vacuum to give the desired hydrochloride.

was synthesised in analogy to Intermediate 48b, starting fromIntermediate 47c.

3-(trifluoromethyl)benzaldheyde (6.46 ml, 48.24 mmol) was dissolved in80 ml of dry tetrahydrofurane, the reaction mixture was cooled to −78°C. and a 0.5M solution of 3-butenylmagnesiumbromide in tetrahydrofurane(106.13 ml, 53.06 mmol) was added dropwise over 30 minutes. The reactionmixture was stirred at −78° C. for 30 minutes. Then, the reactionmixture was allowed to reach room temperature and stirred 18 h. Then,100 ml of a saturated aqueous solution of ammonium chloride and 200 mlof ethyl acetate were added. the organic layer was separated, dried oversodium sulfate and concentrated under vacuum. 7.75 g (33.69 mmol) of thedesired product were obtained.

Intermediate 49a was dissolved in 70 ml of dry dichloromethane, thereaction mixture was stirred under nitrogen atmosphere at 0° C. andN-bromosuccinimmide was added. The reaction mixture was allowed to reachroom temperature and stirred for 48 h. The reaction mixture wasconcentrated under vacuum. The crude product was purified by flashchromatography (Isolera cartridge eluent: hexane/ethyl acetate=90/10%)to obtain the desired product as diastereoisomeric mixture.

Intermediate 50a was purified by flash chromatography (Isoleracartridge; eluent: hexane/ethyl acetate=98/2%). 2.3 g (7.44 mmol) of thetrans diastereoisomer were obtained as racemic mixture (relativestereochemistry assigned by NMR).

Further elution of the column gave 1.05 g (3.39 mmol) of the cisdiastereoisomer as racemic mixture (relative stereochemistry assigned byNMR).

The following intermediates were synthesized in analogy to Intermediates49a, 50a, 51a and 52a

Starting Inter- Inter- Inter- Inter- aldehyde mediate STRUCTURE mediateSTRUCTURE mediate STRUCTURE mediate STRUCTURE 3-Methyl- benzaldheyde 49b

50b

51b

52b

4-Methyl- benzaldheyde 49c

50c

51c

52c

4-Fluoro-3- methyl- benzaldheyde 49d

50d

51d

52d

3-Fluoro-4- methyl- benzaldheyde 49e

50e

51e

52e

4-Chloro- benzaldheyde 49f

50f

51f

52f

4- Trifluoro- methyl- benzaldheyde 49g

50g

51g

52g

Intermediate 50a (1.7 g, 5.49 mmol) was dissolved in 5 ml of DMSO andthe reaction mixture was stirred under nitrogen atmosphere at roomtemperature. Phtalimide potassium salt (2.54 g, 13.75 mmol) and sodiumiodide (240 mg, 1.60 mmol) were added and the reaction mixture wasstirred at 70° C. for 18 h. The reaction mixture was cooled to roomtemperature and diluted with 40 ml of a saturated aqueous sodiumbicarbonate solution and with 100 ml of ethyl acetate. The organic layerwas separated, dried on sodium sulfate and concentrated under vacuum.The crude product was purified by flash chromatography (Isoleracartridge; eluent: hexane/ethyl acetate=85/15%) to yield 1.2 g (3.2mmol) of the phtalimido intermediate. The phtalimido intermediate (1.2g, 3.2 mmol) was dissolved in 15 ml of methanol. Hydrazine hydrate (1.24ml, 25.60 mmol) was added and the reaction mixture was stirred at roomtemperature for 48 h. The reaction mixture was concentrated undervacuum. The crude product was dissolved in 10 ml of dichlorometane, theorganic layer was washed with water, separated, dried on sodium sulfateand concentrate under vacuum. 474 mg (1.93 mmol) of the desired productwere obtained.

was synthesized in analogy to Intermediate 53a starting fromintermediate 51a

was synthesized in analogy to Intermediates 53a starting fromintermediate 52a.

The following intermediates were synthesized in analogy to Intermediates53a, 54a and 55a.

Starting Inter- Inter- mediate mediate STRUCTURE 50b 53b

50c 53c

50d 53d

50e 53e

50f 53f

50g 53g

2- bromomethyl- 4-phenyl- tetrahydro- furan 53h

51b 54b

51c 54c

51d 54d

51e 54e

51f 54f

51g 54g

52e 55e

52b 55b

52c 55c

52d 55d

52f 55f

52g 55g

2,3-Dihydro-pyrano[3,2-b]pyridine-4-one (250 mg, 1.7 mmol) andRaney-Nickel (25 mg) were added to a solution of ammonia in ethanol (10ml) and the reaction mixture was stirred under hydrogen atmosphere (3bar) for 18 h at room temperature. Then, the catalyst was removed byfiltration on a celite pad and the mixture was concentrated undervacuum. The residue was purified by reversed phase HPLC to give thedesired product (129 mg, 600 μmol).

Synthesis of Examples

E and G within the scope of this invention denotes C or N, preferrednitrogen.

The examples of this invention are synthesized according to thefollowing general synthetic procedures:

Synthetic Procedure A:

Examples: 1-159gc; 289-302 Synthetic Procedure B:

Examples: 160-247; 228a; 228ga-228gn; 229-247

Examples: 286-288

Examples: 228b-228g; 228go; 228gp

Synthetic Procedure C:

Examples: 248-283; 275a-275dj

Example 1

Intermediate 25b (70 mg, 0.16 mmol), 4-tert-butyl-benzylamine (32 mg,0.19 mmol) and N,N-diisopropyl-ethyl amine (0.042 ml, 0.24 mmol) in 2 mlof dry 1,4-dioxane were stirred at 70° C. overnight. The reactionmixture was concentrated under vacuum and the crude product wasdissolved in dichloromethane. The organic phase was washed with asaturated aqueous sodium bicarbonate solution, dried over sodium sulfateand concentrated under vacuum. The crude product was purified by flashchromatography (Silica Isolute cartridge 5 g; eluent: ethylacetate/methanol=90/10%). 16 mg (0.027 mmol) of the desired product wereobtained. HPLC (Method 2F): R_(t). (min)=7.59

[M+H]⁺=557

The following examples were synthesized in analogy to the preparation ofExample 1.

HPLC Inter- [M + R_(t•) Meth- Ex # STRUCTURE mediate Amine H]⁺ (min) od2

25i 2-(3,4- dichloro- phenyl)- ethyl- amine 476 7.98 1E 3

25f 2-(3,4- dichloro- phenyl)- ethyl- amine 492 2.91 B 4

25f 3- trifluoro methyl- benzyl- amine 478 6.77 1E 5

25f 4- trifluoro- methoxy- benzyl- amine 494 6.78 1E 6

25f 3-fluoro- 5- trifluoro methyl- benzyl- amine 496 6.73 1E 7

25f 4-tert- butyl- benzyl- amine 466 7.45 1E 8

25f 3- trifluoro methoxy- benzyl- amine 494 7.08 1E 9

25f 4- trifluoro methyl- benzyl- amine 478 6.63 1E 10

25f 3-fluoro- 4- trifluoro methyl- benzyl- amine 496 6.85 1E 11

25f 2-(3- trifluoro methyl- phenyl)- ethyl- amine 492 7.23 1E 12

25f 2-(4- trifluoro methyl- phenyl)- ethyl- amine 492 7.37 1E 13

25f (4- (trifluoro- methyl)- cyclo- hexyl)- methan- amine 484 6.82 1E 14

25f 2-(4- trifluoro- methoxy- phenyl)- ethyl- amine 508 7.37 1E (Fusion)15

25f 4-phenyl- butyl- amine 452 7.15 1E 16

25f 2- phenoxy- ethyl- amine 440 7.10 1E (Fusion) 17

25f 3-phenyl- propyl- amine 438 7.83 1E (Fusion) 18

25f 2-benzyl- oxy- ethyl- amine 454 5.83 1E (Hydro) 19

25f chroman- 3-yl- methan- amine 466 7.85 1E (Fusion) 20

25f (1- phenyl- pyrrol- idin-3- yl)- methan- amine 479 7.05 1E (Hydro)21

25f 2-fluoro- 4- trifluoro methyl- benzyl- amine 496 8.38 1E (Fusion) 22

25f 4-phenyl- cyclo- hexyl- amine 478 9.38 1E (Fusion) 23

25f indan-2- yl- methan- amine 450 6.55 1E (Hydro) 24

25f chroman- 3- ylamine 452 6.18 1E (Hydro) 25

25f (R)- (1,2,3,4- tetra- hydro- naphtal- en-2- yl)amine 450 7.08 1E(Hydro) 26

25f (1,2- dihydro- cyclo- buta- benzen- 1-yl)- methan- amine 436 6.93 1E(Hydro) 27

25f (2,3- dihyro- benzofu- ran-2- yl)- methan- amine 452 6.47 1E (Hydro)28

25f Cyclo- hexyl- amine 402 4.90 1E 29

25f benzofu- ran-5- ylmethan amine 450 6.73 1E (Hydro) 30

25f 3-chloro- 4- methyl- benzyl- amine 458 7.75 1E (Hydro) 31

25f 3,4- dime- thyl- benzyl- amine 438 7.37 1E (Hydro) 32

25c 3-chloro- 4- methyl- benzyl- amine 563 6.98 2F 33

25c 3-chloro- 4- trifluoro methyl- benzyl- amine 617 9.47 1E (Hydro) 34

25c 4- isopro- pyl- benzyl- amine 557 7.03 2F 35

25c 3,4- dichloro- benzyl- amine 583 8.65 1E (Hydro) 36

25c 2-(3,4- dichloro- phenyl)- ethyl- amine 597 9.72 1E (Hydro) 37

25c 4-tert- butyl- benzyl- amine 571 9.28 1E (Hydro) 38

25c 9a 598 1.45 2F 39

25c 4-chloro- 3-fluoro- benzyl- amine 567 8.82 1E (Hydro) 40

25c (1- phenyl- piper- idin- 4yl)- methan- amine 598 8.98 1E (Hydro) 41

25c 9b 584 8.92 1E (Hydro) 42

25h 9a 479 8.67 1E (Hydro) 43

25h 3-chloro- 4- methyl- benzyl- amine 444 8.63 1E (Hydro) 44

25h 3-fluoro- 4- methyl- benzyl- amine 428 7.58 1E (Hydro) 45

25h 4-chloro- 3-fluoro- bemzyl- amine 448 7.88 1E (Hydro) 46

25h indan- 2yl- methan- amine 436 8.27 1E (Hydro) 47

25h 3-chloro- 4- trifluoro methyl- benzyl- amine 498 7.30 2F 48

25h 3,4- difluoro- benzyl- amine 432 4.20 2G 49

25b 4-chloro- benzyl- amine 535 7.38 2F 50

25h chroman- 3- ylmethan amine 452 7.85 1E (Hydro) 51

25h (1- phenyl- pyrrol- idin-3- yl)- methan- amine 465 8.93 1E (Hydro)52

25h 4-tert- butyl- benzyl- amine 452 7.18 2F 53

25b 2-(3,4- dichloro- phenyl)- ethyl- amine 583 7.97 1E (Hydro) 54

25b (6-tert- butyl- pyridin- 3-yl)- methan- amine 558 7.73 1E (Hydro) 55

25b 4-fluoro- 3- methyl- benzyl- amine 533 8.05 1E (Hydro) 56

25b 4-ethyl- benzyl- amine 529 8.35 1E (Hydro) 57

25b chroman- 3- ylmethan amine 557 7.62 1E (Hydro) 58

25b (1- phenyl- piperi- din-4yl)- methan- amine 584 8.05 1E (Hydro) 59

25b 3-chloro- 4- methyl- benzyl- amine 549 8.22 1E (Hydro) 60

25b (1- phenyl- pyrrol- idin-3- yl)- methan- amine 570 8.07- 8.47 1E(Hydro) 61

25b indan- 2yl- methan- amine 541 8.03 1E (Hydro) 62

25b 3-chloro- 4- trifluoro methyl- benzyl- amine 603 8.68 1E (Hydro) 63

25b 4-chloro- 3-fluoro- benzyl- amine 553 7.55 1E (Hydro) 64

25b 4- isopro- pyl- benzyl- amine 543 6.82 2F 65

25b 3-fluoro- 4- methyl- benzyl- amine 533 8.57 1E (Hydro) 66

25b 3-chloro- benzyl- amine 535 6.72 2F 67

25b 4- methoxy- benzyl- amine 531 2.39 2F 68

25b 3-chloro- 4-fluoro- benzyl- amine 553 7.57 2F 69

25a 4-tert- butyl- benzyl- amine 543 7.97 1E (Hydro) 70

25a 4- trifluoro meth- oxy- benzyl- amine 585 7.63 1E (Hydro) 71

25a chroman- 3- ylmethan amine 543 6.75 1E (Hydro) 72

25a 3,4- dichloro- benzyl- amine 555 7.30 1E (Hydro) 73

25a indan- 2yl- methan- amine 527 7.35 1E (Hydro) 74

25a (1- phenyl- pyrrol- idin-3- yl)- methan- amine 555 7.43- 7.80 1E(Hydro) 75

25a 3-chloro- 4- trifluoro methyl- benzyl- amine 589 7.48 2F 76

25a 4-chloro- 3-fluoro- benzyl- amine 539 2.07 1F 77

25e 3-chloro- 4- trifluoro methyl- benzyl- amine 539 8.23 1E (Hydro) 78

25e 4-chloro- 3-fluoro- benzyl- amine 489 7.33 1E (Hydro) 79

25l chroman- 3- ylmethan amine 571 8.13 1E (Hydro) 80

25l 4-chloro- 3-fluoro- benzyl- amine 567 8.36 1E (Hydro) 81

25l 3-chloro- 4- trifluoro methyl- benzyl- amine 617 9.12 1E (Hydro) 82

25l 3,4- dichloro- benzyl- amine 583 8.83 1E (Hydro) 83

25l 4-tert- butyl- benzyl- amine 571 9.73 1E (Hydro) 84

25l (1- phenyl- pyrrol- idin-3- yl)- methan- amine 584 8.70- 9.02 1E(Hydro) 85

25l 9c 584 9.1 1E (Hydro) 86

25l indan- 2yl- methan- amine 555 8.80 1E (Hydro) 87

25l 9a 598 8.97 1E (Hydro) 88

25k 3,4- dichloro- benzyl- amine 569 7.78 1E (Hydro) 89

25k 3-phenyl- cyclo- hexyl- amine 569 8.45 1E (Hydro) 90

25k chroman- 3- ylmethan amine 557 7.20 1E (Hydro) 91

25m 2-(3,4- dichloro- phenyl)- ethyl- amine 506 7.87 1E 92

25m 3,4- dichloro- benzyl- amine 492 7.62 1E 93

25d (1- phenyl- pyrrol- idin-3- yl)- methan- amine 520 7.70 1E (Hydro)94

25g 4- isopro- pyl- benzyl- amine 466 6.71 2F 95

25g 4-chloro- 3-fluoro- benzyl- amine 476 9.18 1E (Hydro) 96

25g (1- phenyl- piper- idin- 4-yl)- methan- amine 507 9.55 1E (Hydro) 97

25g 9a 507 1.22 2F 98

25g 3-chloro- 4- methyl- benzyl- amine 472 9.62 1E (Hydro)

Example 99

Intermediate 2a (200 mg, 1.047 mmol) was dissolved in 30 ml ofdichlorometane. [1,4]Bipiperidinyl-4-ol (192 mg, 1.047 mmol) was addedand the reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was concentrated under vacuum and the crude product wasdissolved in 1 ml of DMSO. Phenethylamine (0.6 ml, 4.73 mmol) andN,N-diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) were added and thereaction mixture was stirred at 80° C. overnight. The reaction mixturewas concentrated under vacuum. The crude product was purified by reversephase preparative HPLC. 331 mg (0.616 mmol) of the desired product wereobtained.

HPLC (Method C): R_(t). (min)=1.34

[M+H]⁺=424

The following examples were synthesized in analogy to the preparation ofExample 99.

HPLC Ex Inter- Inter- R_(t•) Meth- # STRUCTURE mediate mediate Amine[M + H]⁺ (min) od 100

2a [1,4′]- Bipiperi- dinyl- 3-ol Bi- phenyl- 3-yl- methan- amine 4861.53 2C 101

2a [1,4′] Bipiperi- dinyl- 4-ol Bi- phenyl- 4-yl- methan- amine 486 1.512C 102

2a [1,4′] Bipiperi- dinyl- 4-ol Bi- phenyl- 3-yl- methan- amine 486 1.522C 103

6- chloro- pyri- midine- 4- carbonyl chloride [1,4′]- Bipiperi- dinyl-3-ol Bi- phenyl- 4-yl- methan- amine 472 1.59 2C

Example 104

Intermediate 25i (17 mg, 0.05 mmol), 3-fluoro-4-methyl-benzylamine (10mg, 0.075 mmol) and diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) in 1ml of dry DMSO were stirred at 80° C. overnight. The reaction mixturewas concentrated under vacuum. The crude product was purified by reversephase preparative HPLC. 20 mg (0.047 mmol) of the desired product wereobtained.

HPLC (Method C): R_(t). (min)=1.45

[M+H]⁺=426

The following examples were synthesized in analogy to the preparation ofExample 104.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Amine [M + H]⁺ (min) Method105

25f 2-(3- chloro-4- methoxy- phenyl)- ethyl- amine 488 1.43 2C 106

25f 2-(4- isopropyl- phenyl)- ethylamine 466 2.88 2B 107

25h 3,4- dichloro- benzyl- amine 464 5.6 1A 108

25f Cyclohexyl- methan- amine 416 2.67 2B 109

25f 3,4- dichloro- benzyl- amine 478 2.81 2B 110

25f 4-chloro- benzyl- amine 444 1.6 2A 111

25f 3-chloro-4- fluoro- benzyl- amine 462 1.63 2A 112

25f 2-(4-tert- butyl- phenyl)- ethylamine 480 1.8 2A 113

25f (1-phenyl- piperidin- 4- yl)methan- amine 493 1.32 2A 114

25f 7a 492 7.42 2F 115

25f 2-(3,4- difluoro- phenyl)- ethylamine 460 1.61 2A 116

25f 3-chloro-4- trifluoro- methyl- benzyl- amine 512 1.74 2A 117

25f 4-chloro-3- fluoro- benzyl- amine 462 1.64 2A 118

25f 4-fluoro-3- methyl- benzyl- amine 442 1.61 2A 119

25f 2-(3- chloro-4- methoxy- phenyl)- ethyl- amine 488 1.63 2A 120

25f 3-fluoro-4- methyl- benzyl- amine 442 1.61 2A 121

25f (4- phenylcyclo- hexyl)- methan- amine 492 1.78 2A 122

25f 2-(3-chloro- phenyl)- ethylamine 458 1.63 2A 123

25f 3-chloro- benzyl- amine 444 1.6 2A 124

25f 2-(4-chloro- phenyl)- ethylamine 458 1.65 2A 125

25f 4-chloro-3- trifluoro- methyl- benzyl- amine 512 1.74 2A 126

25f 2-(3,4- dimethyl- phenyl)- ethylamine 452 1.68 2A 127

25i 4-chloro- benzyl- amine 428 1.65 2A 128

25i 3-chloro-4- fluoro- benzyl- amine 446 1.67 2A 129

25i 2-(4-tert- butyl- phenyl)- ethylamine 464 1.84 2A 130

25i (1-phenyl- piperidin- 4-yl)- methan- amine 477 1.37 2A 131

25i 7a 476 1.84 2A 132

25i 2-(3,4- difluoro- phenyl)- ethylamine 444 1.66 2A 133

25i 3-chloro-4- trifluoro- methyl- benzyl- amine 496 1.79 2A 134

25i 4-chloro-3- fluoro- benzyl- amine 446 1.67 2A 135

25i 4-fluoro-3- methyl- benzyl- amine 426 1.65 2A 136

25i 2-(3- chloro-4- methoxy- phenyl)- ethylamine 472 1.66 2A 137

25i 3-fluoro-4- methyl- benzyl- amine 426 1.65 2A 138

25i (4- phenylcyclo- hexyl)- methan- amine 476 1.84 2A 139

25i 2-(3- chloro- phenyl)- ethylamine 442 1.68 2A 140

25i 3-chloro- benzyl- amine 428 1.64 2A 141

25i 2-(4- chloro- phenyl)- ethylamine 442 1.69 2A 142

25i 4-chloro-3- trifluoro- methyl- benzyl- amine 496 1.79 2A 143

25i 2-(3,4- dimethyl- phenyl)- ethylamine 436 1.72 2A 144

25f 7a 492 7.7 2H (iso- cratic) 145

25f 7a 492 10.2 2H (iso- cratic)

Example 146

Intermediate 25b (80 mg, 0.18 mmol), Intermediate 7c (40 mg, 0.21 mmol)and N,N-diisopropyl-ethyl amine (0.046 ml, 0.26 mmol) in 0.2 ml of dry1,4-dioxane were mixed in a microwave vial and reacted in the followingconditions: Power 100, Ramp 5 min, Hold 2 h, Temperature 150° C.,Pression 150° C., Stirring. The reaction mixture was concentrated undervacuum and diluted with dichloromethane. The organic phase was washedwith an aqueous saturated sodium bicarbonate solution, dried over sodiumsulfate and concentrated under vacuum. The crude product was purified byreverse phase preparative HPLC. 36 mg (0.06 mmol) of the desired productwere obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.52

[M+H]⁺=583

The following examples were synthesized in analogy to the preparation ofExample 146

In- ter- me- HPLC Ex di- [M + R_(t•) Meth- # STRUCTURE ate Amine H]⁺(min) od 147

25c (trans- 2- phenyl- cyclo- propyl) methan- amine 555 8.48 1E (Hy-dro) 148

25b (1,2, 3,4- tetra- hydro- naph- thalen- 1-yl)- methan- amine 555 8.621E (Hy- dro) 149

25b 9c 570 8.7 1E (Hy- dro) 150

25b 7d 583 9.12 1E (Hy- dro) 151

25b 7e 583 9.22 1E (Hy- dro) 152

25b (trans- 2- phenyl- cyclo- propyl) methan- amine 541 8.03 1E (Hy-dro) 153

25b 2-(4- tert- butyl- phenyl)- ethyl- amine 571 9.42 1E (Hy- dro) 154

25b 1l 643 8.65 1E (Hy- dro) 155

25b 9a 584 8.52 1E (Hy- dro) 156

25b 9b 570 8.48 1E (Hy- dro) 157

25b Quin- olin- 3- yl- methan- amine 552 1.28 2F 158

25b 7b 583 9.48 1E (Hy- dro) 159

25l 9b 584 8.85 1E (Hy- dro) 159a

25n 7a 613 2.21 2Ca 159b

25n 4-tert- butyl- benzyl- amine 587 1.89 2Ca 159c

25b 7m 603 9.88 1E (Hy- dro) 159d

25b 7l 569 9.62 1E (Hy- dro) 159e

25b C- Cyclo- hexyl- methyl- amine 507 8.37 1E (Hy- dro) 159f

25b C-(4- iso- propyl- cyclo- hexyl)- methyl- amine 549 10.12 1E (Hy-dro) 159g

25b C-(3- methyl- cyclo- hexyl)- methyl- amine 521 9.25 1E (Hy- dro)159h

25b C- (3,3- di- methyl- cyclo- hexyl)- methyl- amine 535 9.68 1E (Hy-dro) 159i

25d 7a 533 9.53 1E (Hy- dro) 159k

25b C-(4- ethyl- cyclo- hexyl)- methyl- amine 535 9.98 1E (Hy- dro) 159l

25b C-(4- methyl- cyclo- hexyl)- methyl- amine 521 9.28 1E (Hy- dro)159m

25a 7a 569 9.33 1E (Hy- dro) 159n

25b C-(3- pyri- din- 2yl- cyclo- hexyl)- methyl- amine 584 7.90 8.05 1E(Hy- dro) 159o

25b C-(4- tert- butyl- cyclo- hexyl)- methyl- amine 563 10.87 1E (Hy-dro) 159p

25d 7c 533 9.53 1E (Hy- dro) 159q

25b 7n 587 9.37 1E (Hy- dro) 159r

25b C-[4- (1H- Benzo- imida- zol- 2-yl)- cyclo- hexyl]- methyl- amine623 7.17 1E (Hy- dro) 159s

25b C-[(4- phenyl- mor- pho- lin- 2-yl)- methyl- amine 586 7.73 1E (Hy-dro) 159t

25b C-(1- pheny- cyclo- hexyl)- methyl- amine 583 9.5 1E (Hy- dro) 159u

25b C-(5- pheny- furan- 2yl)- methyl- amine 567 8.93 1E (Hy- dro) 159w

25b 9d 652 9.57 1E (Hy- dro) 159y

25b 2-(1- methyl- 1H- indol- 3yl)- ethyl- amine 568 8.2 1E (Hy- dro)159x

25b C- Indan- 1-yl- methyl- amine 541 8.27 1E (Hy- dro) 159z

25b 7g 601 9.8 1E (Hy- dro) 159 aa

25d 7g 551 9.47 1E (Hy- dro) 159 ba

25a 7g 587 9.32 1E (Hy- dro) 159 ca

25a 7f 603 9.95 1E (Hy- dro) 159 da

25b 7f 617 10.5 1E (Hy- dro) 159 ea

25d 7f 567 7.4 2F 159 fa

25b C- cyclo- heptyl- methyl- amine 521 8.88 1E (Hy- dro) 159 ga

25l 54a 653 5.38 2M 159 ha

25b 54a 639 5.94 2M 159 ia

25b 54b 585 5.42 2M 159 ja

25l 54b 599 4.76 2M 159 ka

25l 55g 653 9.37 1E (Hy- dro) 159 la

25b 55g 639 9.02 1E (Hy- dro) 159 ma

25b 54g 639 9.07 1E (Hy- dro) 159 na

25b 53e 603 8.6 1E (Hy- dro) 159 oa

25l 53c 599 9.01 1E (Hy- dro) 159 pa

25b 53a 639 8.38 1E (Hy- dro) 159 qa

25l 53a 653 8.85 1E (Hy- dro) 159 ra

25b 53b 585 7.86 1E (Hy- dro) 159 sa

25l 53b 599 8.36 1E (Hy- dro) 159 ta

25l 53e 617 9.03 1E (Hy- dro) 159 ua

25l 54f 619 8.63 1E (Hy- dro) 159 wa

25b 54f 605 8.10 1E (Hy- dro) 159 ya

25l 54d 617 5.08 2M 159 xa

25b 7h 613 9.95 1E (Hy- dro) 159 za

25b 7i 597 10.52 1E (Hy- dro) 159 ab

25b 53f 605 9.0 1E (Hy- dro) 159 bb

25b C-(3- methyl- cyclo- pentyl)- methyl- amine 507 8.53 1E (Hy- dro)159 cb

25b 53c 585 8.77 1E (Hy- dro) 159 db

25b 7j 601 10 1E (Hy- dro) 159 eb

25b 53h 571 7.93 1E (Hy- dro) 159 fb

25b C-(5- phenyl- tetra- hydro furan- 3yl)- methyl- amine 571 7.83 1E(Hy- dro) 159 gb

25b 54c 585 8.36 1E (Hy- dro) 159 hb

25b 53g 639 8.94 1E (Hy- dro) 159 ib

25l 53g 653 9.27 1E (Hy- dro) 159 jb

25b 55c 585 8.38 1E (Hy- dro) 159 kb

25g 7g 524 2.87 1Fa 159 lb

25g 7f 540 3.02 1Fa 159 mb

25b 7r 567 8.85 1E (Hy- dro) 159 nb

25b C- Bicyclo [4.2.0] octa- 1(6), 2,4- trien- 7-yl- methyl- amine 5277.53 1E (Hy- dro) 159 ob

25b C- Chro- man- 2yl- methyl- amine 557 7.9 1E (Hy- dro) 159 pb

25b C- (1,2, 3,4- Tetra- hydro- naph- thalen- 2-yl-)- methyl- amine 5558.47 1E (Hy- dro) 159 qb

25b C- (2,3- Di- hydro- benzo- furan- 2yl)- methyl- amine 543 7.4 1E(Hy- dro) 159 rb

25b C-(5- Chloro- 2,3- Di- hydro- benzo- furan- 2yl)- methyl- amine 5576.5 2F 159 sb

25b C-(6- Chloro- cro- man- 3-yl)- methyl- amine 591 8.09 1E (Hy- dro)159 tb

25b 7s 589 9.8 1E (Hy- dro) 159 ub

25b 7t 555 9.07 1E (Hy- dro) 159 wb

25b 7u 589 9.7 1E (Hy- dro) 159 yb

25b 7v 555 9.02 1E (Hy- dro) 159 xb

25b 7o 587 9.55 1E (Hy- dro) 159 zb

25b 7k 549 10.37 1E (Hy- dro) 159 ac

25b C- (tetra- hydro- pyran- 4- yl)- methyl- amine 509 5.92 1E (Hy- dro)159 bc

25b C- (tetra- hydro- pyran- 3- yl)- methyl- amine 509 6.15 1E (Hy- dro)159 cc

25l 7o 601 5.40 2M 159 dc

25o C- cyclo- hexyl- methyl- amine 446 1.23 2Gb 159 ec

25o Indan- 2-yl- amine 466 1.24 2Gb 159 fc

25o C- Indan- 2-yl- methyl- amine 480 2.97 2Ga 159 gc

25b C- (1,2, 3,4- Tetra- hydro- quino- lin- 2-yl)- methyl- amine 5561.35 2Ca

Example 160

Intermediate 28b (80 mg, 0.20 mmol), Intermediate 13 (74 mg, 0.30 mmol)and N,N-diisopropyl-ethylamine (0.087 ml, 0.51 mmol) in 2 ml ofdichloromethane were stirred at room temperature for 10 min. Sodiumtriacetoxyborohydride (129 mg, 0.61 mmol) was added and the reactionmixture was stirred at room temperature overnight. The organic phase waswashed with an aqueous saturated sodium bicarbonate solution, dried oversodium sulfate and concentrated under vacuum. The crude product waspurified by reverse phase preparative HPLC. 39 mg (0.06 mmol) of thedesired product were obtained.

HPLC (Method 2F): R_(t). (min)=7.25

[M+H]⁺=583

The following examples were synthesized in analogy to the preparation ofExample 160.

Ex # STRUCTURE 161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

228a

228b

228c

228d

228e

228f

228g

228ga

228gb

228gc

228gd

228ge

228gf

228gg

228gh

228gi

228gj

228gk

228gl

228gm

228gn

228go

228gp

HPLC Ex Inter- Amine or R_(t•) # mediate Ketone [M + H]⁺ (min) Method161 28f N-Methyl- N- piperidin- 4-yl- methane- sulfon- amide 571 7.17 2F162 28f Morpholine 466 9.97- 10.27 1E 163 28f Pyrrolidine 450 7.06 2F164 28a 4,4- difluoro- piperidine 512 8.17 1E 165 28a (R)- pyrrolidin-3-ol 478 7.62 1E 166 28a (S)- pyrrolidin- 3-ol 478 7.57 1E 167 28a 4-fluoro- piperidine 494 7.37 2F 168 28a N- piperidin- 4yl- methan-sulfon- amide 569 7.28 1E (Fusion) 169 28a (S)-N- piperidin- 3yl-methan- sulfon- amide 569 8.50 1E 170 28a N-piperidin- 4yl- isobutyr-amide 561 7.58 1E 171 28a N- piperidin- 4yl- acetamide 533 7.07 2F 17228a Piperidin- 4- carboxylic acid amide 519 7.07 1E (Fusion) 173 28aPiperidin- 4- carboxylic acid methyl- amide 533 7.73 1E (Fusion) 174 28a(R)-N- piperidin- 3yl- methan- sulfon- amide 569 8.48 1E (Fusion) 17528a (S)- piperidine- 3- carboxylic acid amide 519 8.70 1E (Fusion) 17628a (S)- piperidine- 3- carboxylic acid methyl amide 533 7.03 2F 177 28a(S)- piperidine- 3- carboxylic acid dimethyl amide 547 7.15 2F 178 28aN-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide 597 9.62 1E (Hydro)179 28a (S)- piperidine- 3- carboxylic acid 520 6.60 1E (Fusion) 180 28bMethyl- (3-methyl- oxetan- 3yl- methyl)- amine 492 8.05 1E (Hydro) 18128b 2- (methoxy- ethyl)- methyl- amine 466 7.72 1E (Hydro) 182 28bMethyl- amino- acetonitrile 447 8.00 1E (Hydro) 183 28b 2,3- dihydro-1H- isoindole 496 9.52 1E (Hydro) 184 28b 4- trifluoro- methyl-piperidine 530 9.60 1E (Hydro) 185 28b 18 585 7.33 1E (Hydro) 186 28bPiperidin- 4- carboxylic acid methyl- amide 519 7.42 1E (Hydro) 187 28bPiperidin- 4yl-urea 520 7.05 2F 188 28b 2- methan- sulfonyl- 2,8-diazaspiro [4.5]- decane 595 8.32 1E (Hydro) 189 28b 4- (1,1- dioxo-isothiazolidin- 2-yl)- piperidine 581 8.23 1E (Hydro) 190 28b 2,8-diazaspiro [4.5] decan- 1-one 531 7.58 1E (Hydro) 191 28b 16a 585 7.651E (Hydro) 192 28b 1- piperidin- 4-yl- pyrrolidin- 2-one 545 8.08 1E(Hydro) 193 28b Azetidin- 3- carboxylic acid methyl- amide 491 7.55 1E(Hydro) 194 28b N- methyl- N- piperidin- 4yl- acetamide 533 7.87 1E(Hydro) 195 28b Ethan- sulfonic acid- piperidin- 4-yl- amide 569 8.15 1E(Hydro) 196 28c Piperidine- 4- sulfonic acid dimethyl- amide 557 9.11 1E(Hydro) 197 28b Propan- 2- sulfonic acid- piperidin- 4-yl- amide 5838.37 1E (Hydro) 198 28c 4- ethoxy- piperidine 494 10.75 1E (Hydro) 19928c N- piperidin- 4- methyl- methan- sulfonamide 557 9.45 1E (Hydro) 20028c 4-tert- butyl- piperidine 506 7.86 2F 201 28c 4- (piperidin- 4-yl)-pyridine 527 10.88 1E (Hydro) 202 28c Piperidine- 4- carbonitrile 4759.77 1E (Hydro) 203 28c 4- (3,4- difluoro- phenoxy)- piperidine 57811.05 1E (Hydro) 204 28c 2- (piperidin- 4- yloxy)- pyridine 543 10.38 1E(Hydro) 205 28c Propan-2- sulfonic- acid- piperidin- 4-yl-amide 571 9.121E (Hydro) 206 28c N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide571 10.18 1E (Hydro) 207 28g Piperidine- 4- sulfonic acid dimethyl-amide 571 9.67 1E (Hydro) 208 28c 4- methoxy- piperidine 480 2.21 2G 20928c 2- methyl- morpholine 466 3.46 2F 210 28c 3- Phenyl- pyrrolidine 5129.68 2F 211 28c Piperidin- 4- carboxylic acid sec- butyl amide 549 9.531E (Hydro) 212 28c 4-(3,5- dimethyl- [1,2,4]- triazol- 4-yl)- piperidine545 8.93 1E (Hydro) 213 28c 4-(3- methyl- [1,2,4]- oxadriazol- 5-yl)-piperidine 532 8.21 2F 214 28c N-methyl- 2-(R)- (pyrrolidin- 2-yl)acetamide 507 9.35 1E (Hydro) 215 28c N-methyl- 2(S)- (pyrrolidin- 2-yl)acetamide 507 9.24 1E (Hydro) 216 28c N,N- dimethyl- 2-(R)- (pyrrolidin-2-yl) acetamide 521 9.71 1E (Hydro) 217 28c N,N- dimethyl- 2-(S)-(pyrrolidin- 2-yl) acetamide 521 9.72 1E (Hydro) 218 28c 2,6- dimethyl-morpholine 480 8.92 2F 219 28c (R)-3- methoxy- pyrrolidine 466 7.23 2F220 28c (S)-3- methoxy- pyrrolidine 466 7.23 2F 221 28c Piperidine-4-sulfonic acid methylamide 543 8.50 1E (Hydro) 222 28c N- azetidin-3-yl-N- methyl- methane- sulfonamide 529 8.65 1E (Hydro) 223 28c N-azetidin- 3-yl- methane- sulfonamide 515 8.02 1E (Hydro) 224 28c4-methyl- piperidine- 4- carboxylic acid methyl- amide 521 9.00 1E(Hydro) 225 28c 4-phenyl- piperidine 526 10.83 1E (Hydro) 226 28bN-methyl- N-(S)- (pyrrolidin- 3yl)- methane- sulfonamide 555 8.04 1E(Hydro) 227 28b 16b 599 8.13 1E (Hydro) 228 28b Piperidine- 4-sulfonicacid amide 541 7.12 1E (Hydro) 228a 28c Methyl- (tetrahydro- pyran-3-yl)- amine 480 10.05 1E (Hydro) 228b 41b 3- methoxy- tetrahydro-pyran- 4-one 522 9.25 1E (Hydro) 228c 41a 3- methoxy- tetrahydro- pyran-4-one 496 8.87 1E (Hydro) 228d 41a 3-fluoro- tetrahydro- pyran- 4-one484 1E (Hydro) 228e 41a N-carb- ethoxy-3- methoxy- 4- piperidone 5677.42 2F 228f 41a 4- chromanone 514 10.31 1E (Hydro) 228g 41a 43 530 9.761E (Hydro) 228ga 28c 47a 496 5.77 2M 228gb 28c 1-(2- Methoxy- ethyl)-3a,4,5,6,7, 7a- hexahydro- 1H- pyrazolo- [3,4-c] pyridine 546 9.55 1E(Hydro) 228gc 28c 1-((R)-3- Amino- piperidin- 1-yl)- ethanone 507 8.851E (Hydro) 228gd 28c (R)-1- Methane- sulfonyl- piperidin- 3- yllamine543 9.11 1E (Hydro) 228ge 28c 3- Phenoxy- methyl- pyrrolidine 542 10.921E (Hydro) 228gf 28c 3- Pyrrolidin- 3-yl- pyridine 527 10.00 1E (Hydro)228gg 28c 3- Trifluoro methyl- 5,6,7,8- tetrahydro- [1,6] naphthyridine567 7.69 2F 228gh 28c C- (Tetrahydro- pyran- 2-yl) methyl- amine 4802.09 2Cb 228gi 28c 56 515 2.18 2Cb 228gj 28c 1-Oxa- 3,8- diazaspiro[4,5] decan- 2-one 521 8.30 1E (Hydro) 228gk 28c 4- Piperidin- 4-yl-benzonitrile 551 10.35 1E (Hydro) 228gl 28c 4-(3,4- Difluoro- benzyl)-piperidine 576 11.42 1E (Hydro) 228gm 28c 8-Aza- bicyclo [3.2.1] octan-3-ol 492 9.30 1E (Hydro) 228gn 28c 45 496 5.96 2M 228go 41a 3- Methoxy-tetrahydro- pyran- 4-one 508 5.77 2M 228gp 41a 3- Tetrazol- 2-yl-tetrahydro- pyran- 4-one 534 7.09 2F

Example 228h

Example 228b (22 mg, 0.032 mmol), formaldehyde (0.003 ml, 0.096 mmol),N,N-diisopropyl-ethylamine (0.008 ml, 0.048 mmol) and trifluoroaceticacid (0.005 ml) in 1.5 ml of methanol were stirred at room temperaturefor 5 min. Sodium cyanoborohydride (10 mg, 0.160 mmol) was added and thereaction mixture was stirred at room temperature overnight. The organicphase was concentrated under vacuum. The crude product was purified byflash chromatography (Isolute silica gel cartridge 5 g, eluent: ethylacetate/methanol=7:3%). 8.4 mg (0.016 mmol) of the desired product wereobtained.

The following examples were synthesized in analogy to the preparation ofExample 228h.

Starting HPLC Ex # STRUCTURE example [M + H]⁺ R_(t). (min) Method 228ha

228ga 510 5.72 2M

Example 229

Intermediate 28a (100 mg, 0.25 mmol), (S)-3-hydroxypiperidine (67 mg,0.49 mmol) and trimethylorthoformate (1.07 ml, 9.82 mmol) in 5 ml ofmethanol were stirred at 60° C. for 1 h. 2-picoline borane complex (26mg, 0.25 mmol) was added and the reaction mixture was stirred at 60° C.overnight. The reaction mixture was concentrated under vacuum. The crudeproduct was purified by reverse phase preparative HPLC. 64 mg (0.13mmol) of the desired product were obtained.

HPLC (Method 1E): R_(t). (min)=7.18

[M+H]⁺=492

The following examples were synthesized in analogy to the preparation ofExample 229.

Inter- HPLC Ex # STRUCTURE mediate Amine [M + H]⁺ R_(t). (min) Method230

28a 1- piperazin- l-yl- ethanone 519 7.13 2F 231

28a (R)- piperidin- 3-ol 492 7.35 1E (Fusion) 232

28a (R)- pyrrolidin- 3- carboxylic acid amide 505 7.83 1E (Fusion) 233

28b 3-fluoro- piperidine 480 8.32 1E (Hydro)

Example 234

Intermediate 28d (20 mg, 0.05 mmol), 2-methyl-morpholine (0.012 ml, 0.10mmol), sodium triacetoxyborohydride (43 mg, 0.20 mmol), acetic acid(0.05 ml) and trimethylorthoformate (0.05 ml) in 0.9 ml of DMA werestirred at room temperature for 3 h. The reaction mixture wasconcentrated under vacuum. The crude product was purified by reversephase preparative HPLC. 3 mg (0.006 mmol) of the desired product wereobtained.

HPLC (Method A): R_(t). (min)=1.74

[M+H]⁺=486

The following examples were synthesized in analogy to the preparation ofExample 234.

Inter- HPLC Ex # STRUCTURE mediate Amine [M + H]⁺ R_(t). (min) Method235

28b Azepane 476 1.72 2A 236

28d Dimethyl- piperidin- 4yl-amine 513 1.64 2A 237

28a 2-methyl- morpho- line 492 1.72 2A 238

28b Pyrrolidin- 3-ol 464 1.65 2A 239

28d Pyrrolidin- 3-ol 472 1.71 2A 240

28a 2-phenyl- morpho- line 554 1.84 2A 241

28a Pyrrolidin- 3-ol 478 1.68 2A 242

. 28b [1,4]-oxa- zepane 478 1.66 2A 243

28d [1,4]-oxa- zepane 486 1.72 2A 244

28b 4,4- difluoro- piperidine 498 1.72 2A 245

28b Azepan- 4-ol 492 1.65 2A 246

28a (3S,4R)- piperidine- 3,4-diol 508 1.66 2A 247

28a Azepan- 4-ol 506 1.68 2A

Example 248

Intermediate 27e (105 mg, 0.33 mmol), TBTU (215 mg, 0.67 mmol) andN,N-diisopropyl-ethylamine (0.12 ml, 0.67 mmol) in 2 ml DMF were stirredat room temperature for 5 min.

Intermediate 20f (100 mg, 0.33 mmol) was added and the reaction mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated under vacuum and the crude product was dissolved indichloromethane. The organic phase was washed with an aqueous saturatedsodium bicarbonate solution, dried over sodium sulfate and concentratedunder vacuum. The crude product was purified by flash chromatography (SiIsolute cartridge (5 g); eluent: ethyl acetate/methanol=90/10%). 30 mg(0.057 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.2

[M+H]⁺=521

The following examples were synthesized in analogy to the preparation ofExample 248.

Inter- HPLC Ex # STRUCTURE mediate Amine [M + H]⁺ R_(t). (min) Method249

27i  20a 568 10.07 1E (Hydro) 250

27c 1- pyrrolidin- 3-yl- piperidine 436 1.5 1E (Hydro) 251

27c [1,3′]- Bipyrro- lidinyl 422 10.35 1E (Hydro) 252

27a [1,4′]- Bipiper- idinyl-4′ carboxylic acid amide 519 8.60 1E(Fusion) 253

27a 4- pyrrolidin- 1yl- piperidine 462 7.07 2F 254

27b  20g 555 7.50 1E (Hydro) 255

27b  20a 569 8.15 1E (Hydro) 256

27b  20j 491 7.03 1E (Hydro) 257

27b  20i 505 7.43 1E (Hydro) 258

27b  20d 541 7.50 1E (Hydro) 259

27b  20c 541 7.48 1E (Hydro) 260

27b  20h 505 7.85 1E (Hydro) 261

27c  20f 507 8.70 1E (Hydro) 262

27e  20g 557 9.11 1E (Hydro) 263

27c  20m 587 8.79 2F 264

27c  20e 557 8.85 1E (Hydro) 265

27c 201 479 8.37 1E (Hydro) 266

27e  20f 521 9.2 1E (Hydro) 267

27e 201 493 8.93 1E (Hydro) 268

39b  20a 542 3.54 2F 269

39b 4- piperidin- 4-yl- morpho- line 436 7.46 2F 270

39a  20a 553 8.28 2F 271

39a 4- piperidin- 4-yl- morpho- line 449 7.60 2F 272

39c  20a 556 7.98 2F 273

39c 4- piperidin- 4-yl- morpho- line 450 7.29 2F 274

39d 24 554 8.28 1E (Hydro) 275

39d [1,4′]- bipiperidin yl-4-ol 477 7.77 1E (Hydro) 275a

27c 201a 480 10.03 1E (Hydro) 275b

27c 201b 510 9.48 1E (Hydro) 275c

27c 201c 508 10.27 1E (Hydro) 275d

27c 201d 514 10.13 1E (Hydro) 275da

27hc 201g 526 9.16 1E (Hydro) 275db

27hd 201g 526 9.18 1E (Hydro) 275dc

27hs 201g 508 7.25 1F 275dd

27hf 201f 494 6.53 2F 275de

27hr 201g 508 8.55 1E (Hydro) 275df

27he 201g 494 8.07 1E (Hydro) 275dg

27hf 201g 494 8.10 1E (Hydro) 275dh

27ha 201f 522 9.03 1E (Hydro) 275di

27ha 201g 522 9.00 1E (Hydro) 275dj

27ha 201a 536 9.76 1E (Hydro) 275dk

27ib  20a 595 2.16 2Cb 275dl

27ic  20a 593 2.20 2Cb

Example 276

Intermediate 27g (50 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol) andN,N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol) in 2 ml DMF were stirredat room temperature for 5 min. 4-piperidin-4-yl-morpholine (24 mg, 0.14mmol) was added and the reaction mixture was stirred at room temperature3 h. The reaction mixture was concentrated under vacuum and the crudeproduct was dissolved in dichloromethane. The organic phase was washedwith an aqueous saturated sodium bicarbonate solution, dried over sodiumsulfate and concentrated under vacuum. The crude product was purified byreverse phase preparative HPLC. 80 mg (0.13 mmol) of the desired productwere obtained.

HPLC (Method C): R_(t). (min)=1.57

[M+H]⁺=486

The following examples were synthesized in analogy to the preparation ofExample 276.

Inter- HPLC Ex # STRUCTURE mediate Amine [M + H]⁺ R_(t). (min) Method277

27h 4-piperidin- 4-yl- morpholine 536 1.69 2C 278

27h [1,4′]- Bipiperidin- yl-4-ol 550 1.65 2C 279

27a 4-piperidin- 4-yl- morpholine 478 1.52 2C 280

27f [1,4′]- Bipiperidin- yl-4-ol 506 1.52 2C 281

27f 4-piperidin- 4-yl- morpholine 492 1.53 2C 282

27g [1,4′]- Bipiperidin- yl-4-ol 500 1.55 2C 283

39e [1,4']- Bipiperidin- yl-4-ol 484 1.66 2C

Example 284

Intermediate 30 (45 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.05ml, 0.27 mmol) were dissolved in 5 ml of dichloromethane. The reactionmixture was stirred at 0° C. and isobutyrylchloride (0.01 ml, 0.09 mmol)was added. The reaction mixture was stirred at 0° C. for 20 min, then itwas washed with an aqueous saturated sodium bicarbonate solution, driedover sodium sulfate and concentrated under vacuum. The crude product wassuspended and stirred in diisopropyl ether, the solid filtered off toobtain 30 mg (0.05 mmol) of the desired compound.

HPLC (Method 1E): R_(t). (min)=7.02

[M+H]⁺=547

The following examples were synthesized in analogy to the preparation ofExample 284.

HPLC Ex # STRUCTURE Intermediate Chloride [M + H]⁺ R_(t). (min) Method285

30 Methane- sulfonyl chloride 555 6.91 2F

Example 286

Intermediate 32 (100 mg, 0.26 mmol) and cyclopentanone (0.02 ml, 0.26mmol) in 2 ml of dichloromethane were stirred at room temperature for 10min. Sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was washed with an aqueous saturated sodium bicarbonatesolution, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by reverse phase preparative HPLC. 31 mg(0.07 mmol) of the desired product were obtained.

HPLC (Method 2F): R_(t). (min)=7.52

[M+H]⁺=450

The following examples were synthesized in analogy to the preparation ofExample 286.

Inter- HPLC Ex # STRUCTURE mediate Ketone [M + H]⁺ R_(t). (min) Method287

32 Acetone 424 7.24 2F 288

32 Tetrahydro- pyran-4-one 466 7.18 2F

Example 289

Intermediate 25b (200 mg, 0.46 mmol) 4-tert-butylphenylboronic acid (99mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium (53 mg, 0.05 mmol)and 0.56 ml of a 2M aqueous solution of sodium carbonate in 2 ml of1,2-dimethoxyethane were stirred at 80° C. overnight. After cooling toroom temperature, water was added and the reaction mixture was extractedwith dichloromethane. The organic phase was washed with an aqueoussaturated sodium bicarbonate solution, dried over sodium sulfate andconcentrated under vacuum. The crude product was purified by flashchromatography (Si Isolute cartridge (5 g); eluent: ethylacetate/methanol=95/5%). 41 mg (0.08 mmol) of the desired product wereobtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.93

[M+H]⁺=528

Example 290

Intermediate 25b (60 mg, 0.14 mmol) and 4-chlorophenol (0.014 ml, 0.14mmol) were dissolved in 2 ml of DMF. Cesium carbonate (45 mg, 0.14 mmol)was added and the reaction mixture was stirred at room temperatureovernight. The solvent was concentrated under vacuum, the crude productwas dissolved in dichloromethane and the organic phase was washed withwater, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by flash chromatography (Si Isolute cartridge(5 g); eluent: dichlorometane/ethyl acetate=90/1%). 50 mg (0.09 mmol) ofthe desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=8.9

[M+H]⁺=522

The following example was synthesized in analogy to the preparation ofExample 290.

Inter- HPLC Ex # STRUCTURE mediate Phenol [M + H]⁺ R_(t). (min) Method291

25b 4-tertbutyl- phenol 544 7.64 2F

Example 292

Sodium hydride (19 mg, 0.46 mmol) and 4-chloro-3-methylbenzylalcohol (44mg, 0.28 mmol) were suspended in 5 ml of dry tetrahydrofuran. Thereaction mixture was stirred at room temperature for 10 min, thenIntermediate 25b (100 mg, 0.23 mmol) was added. The reaction mixture wasstirred at 50° C. overnight. The solvent was concentrated under vacuum,the crude product was dissolved in dichloromethane and the organic phasewas washed with water, dried over sodium sulfate and concentrated undervacuum. The crude product was purified by flash chromatography (SiIsolute cartridge (5 g); eluent: dichlorometane/methanol=95/5%). 40 mg(0.07 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.95

[M+H]⁺=550

The following examples were synthesized in analogy to the preparation ofExample 292.

Inter- HPLC Ex # STRUCTURE mediate Phenol [M + H]⁺ R_(t). (min) Method293

25b 4-hydroxy- methyl- benzonitrile 527 8.17 1E (Hydro) 294

25b (3-fluoro-4- methyl- phenyl)- methanol 534 9.12 1E (Hydro) 295

25b (1-phenyl- pyrrolydin- 3-yl)- methanol 571 10.2  1E (Hydro) 296

25b (4-tert- butyl- phenyl)- methanol 558 2.71 1F 297

25f (4-tert- butyl- phenyl)- methanol 466 9.50 1E (Hydro) 298

25h (4-tert- butyl- phenyl)- methanol 453 8.01 2F 299

25a (4-tert- butyl- phenyl)- methanol 544 9.68 1E (Hydro) 300

25d (4-tert- butyl- phenyl)- methanol 508 10.25  lE (Hydro) 301

25n (4-tert- butyl- phenyl)- methanol 588 2.20 2Ca 302

25n (3-Phenyl- cyclohexyl)- methanol 614 2.18 2Ca

1. A compound according to formula (I),

wherein R₁ is -L₁-R₇, wherein L₁ is a linker selected from a bond or agroup selected from among —C₁-C₂-alkylene, and —C₁-C₂-alkenylene whichoptionally comprises one or more groups selected from —O—, —C(O)—, and—NH— in the chain and which is optionally substituted by a groupselected from among —OH, —NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl, wherein thering R₇ is optionally substituted with one or more groups selected fromamong —CF₃, —O—CF₃, —CN, and -halogen, or wherein the ring R₇ isoptionally substituted with one or more groups selected from among—C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₁-C₆-alkenyl, and—C₁-C₆-alkynyl, optionally being substituted by one or more groupsselected from among —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃,—OCF₃, halogen, and ═O, or wherein the ring R₇ is optionally furtherbi-valently substituted on two neighbouring ring atoms, such that anannellated ring is formed by one or more groups selected from among—C₁-C₆-alkylene, —C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which oneor two carbon centers may optionally by replaced by 1 or 2 hetero atomsselected from N, O and S, the bivalent group being optionallysubstituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl,—O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O; wherein R₂ isselected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl, —C₁-C₄-alkyl,—CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂; wherein R₃ is selectedfrom among —H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, —OCH₃,and —CN; wherein R₄ and R₅ are independently selected from among anelectron pair, —H, and a group selected from among —C₁-C₆-alkyl, —NH₂,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′)independently being selected from among —H, and —C₁-C₆-alkyl, andwherein R₄ and R₅ if different from an electron pair or —H areoptionally independently substituted with one or more groups selectedfrom among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylen-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylen-R₁₄,—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇), wherein Q is selected from among—C(O)—, and —SO₂—, wherein R₁₂, R₁₆, are independently selected fromamong —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, wherein R₉, R_(9′), R₁₀,R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′), are independently selectedfrom among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, or wherein R₉ andR_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ and R_(15′) together forma —C₂-C₆-alkylene group, wherein R₁₄ and R₁₇ are independently selectedfrom among —H, —C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, wherein said—C₃-C₈-heterocyclyl optionally comprises nitrogen and/or —SO₂— in thering, and wherein R₁₄ and R₁₇ are optionally substituted with one ormore groups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or wherein R₄ and/or R₅ areindependently a group of the structure -L₂-R₁₈, wherein L₂ is selectedfrom among —NH— and —N(C₁-C₄-alkyl)-, wherein R₁₈ is selected from among—C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein R₁₈ is optionally substituted by one ormore groups selected from among halogen, —CF₃, —OCF₃, —CN, —OH,—O—C₁-C₄-alkyl, —C₁-C₆-alkyl, —NH—C(O)—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl,—NH—S(O)₂—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and—C(O)—O—C₁-C₆-alkyl, and wherein R₄, R₅ and R₁₈ are optionally furthersubstituted by spiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl suchthat together with R₄, R₅ and/or R₁₈ a spirocycle is formed, whereinsaid spiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring, or wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more spirocyclic or annellated ring forming groupsselected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and—C₄-C₆-alkynylene, in which one or two carbon centers may optionally bereplaced by one or two hetero atoms selected from among N, O and S andwhich may optionally be substituted by one or more groups on one ringatom or on two neighbouring ring atoms selected from among —OH, —NH₂,—C₁-C₃-alkyl, O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen; wherein R₆is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl, -halogen,—CN, —CF₃, and —OCF₃; wherein A is selected from among a single bond,═CH—, —CH₂—, —O—, —S—, and —NH—; wherein n is 1, 2 or 3; wherein Z is Cor N, as well as in form of their acid addition salts withpharmacologically acceptable acids.
 2. The compound of claim 1, whereinR₁ is -L₁-R₇, and wherein L₁ is a bond or a group selected from amongmethylene, ethylene, methenylene, and ethenylene, and wherein R₇ is aring selected from among cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl,tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridyl, andfuranyl, wherein L₁ if different from a bond is optionally substitutedwith one or more groups selected from among methyl, and ethyl, whereinL₁ if different from a bond optionally comprises one or more —O— atoms,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —F, —Cl, -methyl, -ethyl, -propyl, -1-propyl,-cyclopropyl, -t-butyl, —CF₃, —O—CF₃, —CN, —O-methyl, furanyl andphenyl, wherein said furanyl and said phenyl are optionallyindependently substituted by one or more groups selected from among—C₁-C₃-alkyl, halogen, —OCH₃, —CF₃, and —OCF₃, or wherein the ring R₇ isbi-valently substituted by one or more groups selected from among

on two neighbouring ring atoms, such that an annellated ring is formed.3. The compound of claim 1, wherein R₁ is selected from among


4. The compound of claim 1, wherein R₂ is selected from among —H,-methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, -butyl, -i-butyl,-t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, —C≡CH, and —OCH₃.
 5. Thecompound of claim 1, wherein R₂ is selected from among —H, -Methyl,-Ethyl, —Br, and —OCH₃.
 6. The compound of claim 1, wherein R₃ isselected from among —H, and -methyl.
 7. The compound of claim 1, whereinR₄ and R₅ are independently selected from among an electron pair, —H,and a group selected from among-1-propyl, -amino, -pyrrolidinyl,-piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl,-azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and—C(O)—N(R₈,R_(8′)), with R₈ and R_(8′) independently being selected fromamong —H and —C₁-C₆-alkyl, wherein R₄ and R₅ if different from anelectron pair, and —H are optionally independently substituted with oneor more groups selected from among -fluoro, -methyl, -ethyl, propyl,-1-propyl, -butyl, -1-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN,—O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃,—C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂,—NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅,—NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃,—N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂ ⁻ C₂H₅, —N(CH₃)—SO₂—C₂H₅,—N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —H—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇,—N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃) SO₂—C₃H₅,—N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇,—CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅,—NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃,—NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃),—SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇,—C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅,—CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH_(3)—SO)₂—N(CH₃)₂, -phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl,—O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

or wherein R₄ and R₅ are independently a group of the structure -L₂-R₁₈,wherein L₂ is selected from among —NH—, —N(CH₃)—, and —N(C₂H₅)—, andwherein R₁₈ is selected from among -tetrahydropyranyl, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and-tetrahydro-naphthyridinyl, wherein R₁₈ is optionally substituted by oneor more groups selected from among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃,—CH₃, —NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃,—NH—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₃, and —C(O)—O—C₂H₅, and wherein R₄, R₅and R₁₈ are optionally further bi-valently substituted by one or moregroups selected from among

on one ring atom or on two neighboring ring atoms, such that spirocyclicor annellated rings are formed.
 8. The compound of claim 1, wherein R₄is selected from among


9. The compound of claim 1, wherein R₅ is selected from among anelectron pair, —H, and —C(O)—NH₂.
 10. The compound of claim 1, whereinR₆ is selected from among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F, —CF₃,and —OCF₃.
 11. The compound of claim 1, wherein R₆ is H or —O—CH₃. 12.The compound of claim 1, wherein A is selected from a single bond, ═CH—,—CH₂, —O— or —NH—.
 13. The compound of claim 1, wherein A is selectedfrom among —O— and —NH—.
 14. The compound of claim 1, wherein A is —NH—.15. The compound of claim 1, wherein Z is C or N.
 16. (canceled)
 17. Amethod for the treatment of inflammatory diseases comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 1 or a pharmacologicallyacceptable salt thereof.
 18. The method according to claim 17, whereinthe inflammatory diseases are selected from inflammatory diseases of therespiratory tract.
 19. The method according to claim 18, wherein thediseases are selected from chronic obstructive pulmonary disease,asthma, and cystic fibrosis.
 20. A method for the treatment ofneurologic diseases comprising administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 1 or a pharmacologically acceptable salt thereof.
 21. A method forthe treatment of immune related diseases comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1 or a pharmacologically acceptable salt thereof. 22.A method for the treatment of cardiovascular diseases, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 1 or a pharmacologicallyacceptable salt thereof.
 23. A method for the treatment of diabeticnephropathy comprising administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 1 or apharmacologically acceptable salt thereof.
 24. The method according toclaim 20 wherein the neurologic disease is neuropathic pain.
 25. Themethod according to claim 21 wherein the immune related disease isdiabetes mellitus.
 26. The method according to claim 22 wherein thecardiovascular disease is atherosclerosis.